CA2446120A1 - Novel arylheteroalkylamine derivatives - Google Patents

Novel arylheteroalkylamine derivatives Download PDF

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Publication number
CA2446120A1
CA2446120A1 CA002446120A CA2446120A CA2446120A1 CA 2446120 A1 CA2446120 A1 CA 2446120A1 CA 002446120 A CA002446120 A CA 002446120A CA 2446120 A CA2446120 A CA 2446120A CA 2446120 A1 CA2446120 A1 CA 2446120A1
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Prior art keywords
amino
hydroxy
thio
pyridinecarbonitrile
phenylbutyl
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CA002446120A
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French (fr)
Inventor
Tim Birkinshaw
Stephen Connolly
Timothy Luker
Antonio Mete
Ian Millichip
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AstraZeneca AB
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Individual
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Priority claimed from SE0101617A external-priority patent/SE0101617D0/en
Priority claimed from SE0103271A external-priority patent/SE0103271D0/en
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Publication of CA2446120A1 publication Critical patent/CA2446120A1/en
Abandoned legal-status Critical Current

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Abstract

There are provided novel compounds of formula (I) wherein R1, R2, R3, R4, R5 , R6, T, U, X, Y, V and W are as defined in the specification, and pharmaceutically acceptable salts thereof, and enantiomers and racemates thereof; together with processes for their preparation, compositions containing them and their use in therapy. The compounds are inhibitors of nitric oxide synthase and are thereby particularly useful in the treatment o r prophylaxis of inflammatory disease and pain.

Description

NOVEL COMPOUNDS
Field of the Invention s The present invention relates to novel arylheteroalkylamine derivatives, processes for their, preparation, compositions containing them and their use in therapy.
Background of the Invention io Nitric oxide is, produced in mammalian cells from L-arginine by the action of specific nitric oxide synthases (NOSs). These enzymes fall into two distinct classes -constitutive NOS (cNOS) and inducible NOS (iNOS). At the present time, two constitutive NOSs and one inducible NOS have been identified. Of the constitutive NOSs, an endothelial enzyme (ecNOS) is involved with smooth muscle relaxation and the regulation of blood pressure is and blood flow, whereas the neuronal enzyme (ncNOS) serves as a neurotransmitter and appears to be involved in the regulation of various biological functions such as cerebral ischaemia. Inducible NOS has been particularly implicated in the pathogenesis of inflammatory diseases. Regulation of these enzymes should therefore offer considerable potential in the treatment of a wide variety of disease states (J. E.
Macdonald, Ann. Rep.
zo Med. Chem., 1996, 31, 221 - 230).
Considerable effort has been expended in efforts to identify compounds that act as specific inhibitors of one or more isoforms of the enzyme nitric oxide synthase. The use of such compounds in therapy has also been widely claimed.
zs Disclosure of the invention According to the present invention, there is provided a compound of formula (I) X R5 O~R1 T' \- W R2 a U ~ R
'V R6 NH

wherein:
X,represents H, C 1 to 4 alkyl, C 1 to 4 alkoxy, halogen, CN, C=CH, NH2, NHCH3, N(CH3)2, N02, CH20H, CHO, COCH3 or NHCHO; said alkyl or alkoxy group being optionally further s substituted by one or more fluorine atoms;
Y represents C 1 to 4 allcyl, C 1 to 4 alkoxy, halogen, CN, C=CH, N02, CHZOH, CHO, COCH3 or NHCHO; said alkyl or alkoxy group being optionally further substituted by one or more fluorine atoms;
io T, U and W independently represent CR7 or N; and each R7 group independently represents H, F or CH3; and when T represents CR7, the group R7 may additionally represent OH, Cl, Br, CN, CH20H, N02, NHR13, OR14 or OS02CH3;
is V represents O or S(O)n;
n represents an integer 0, l ,or 2;
R1 represents H or Me.
io R2 represents C 1 to 4 alkyl, C2 to 4 alkenyl, C2 to 4, alkynyl, C3 to 6 cycloalkyl or a 4 to 8 membered saturated heterocyclic ring incorporating one heteroatom selected from O, S and N; any of said groups being optionally further substituted by C 1 to 4 alkyl, C 1 to 4 alkoxy, C 1 to 4 alkylthio, C3 to 6 cycloalkyl, halogen or phenyl; said phenyl group being optionally further substituted by one or more substituents selected independently from halogen, C 1 to 4 alkyl, C1 to 4 alkoxy, CF3, OCF3, CN orN02;
or R2 represents phenyl or a five or six membered aromatic heterocyclic ring containing 1 s to 3 heteroatoms independently selected from O, S and N; said phenyl or aromatic heterocyclic ring being optionally substituted by one or more~substituents selected independently from halogen, C 1 to 4 allcyl, C 1 to 4 alkoxy, OH, CN, N02 or NR9R 1 ~; said alkyl or alkoxy group being optionally further substituted by one or more fluorine atoms;
io -R3 represents H, C1 to 4 alkyl or C3 to 6 cycloalkyl; said alkyl group being optionally substituted by C1 to 4 alkoxy, halogen, hydroxy, NR11R12, phenyl or a five or six membered aromatic or saturated heterocyclic ring containing 1 to 3 heteroatoms independently selected from O, S and N; said phenyl or aromatic heterocyclic ring being is optionally further substituted by halogen, C1 to 4 alkyl, CI to 4 alkoxy, CF3, OCF3, CN or N02.
R4, R5, R6, R9, R 1 ~, R 11 ~ R 12~ R 13 ~d R 14 independently represent H or C 1 to.4 alkyl;
zo or a pharmaceutically acceptable salt, enantiomer or racemate thereof.
It will be recognised that compounds of formula (I) wherein U represents N and T
represents CR7 and R~ represents OH may exist in the alternative tautomeric form (Ia):
X R O R~
O
w W R2 a HN / (la) 'V R6 NH

2s It is to be understood that all such possible tautomeric forms and mixtures thereof are included within the scope of the invention.
In one embodiment, X and Y independently represent C 1 to 4 alkyl, C 1 to 4 alkoxy, halogen, CN, C=CH, N02, CHO, COCH3 or NHCHO; said alkyl or allcoxy group being optionally further substituted by one or more fluorine atoms; and T, U and W
independently represent CRS or N; and each R7 group independently represents H, F or CH3.
to The compounds of formula (I) and their pharmaceutically acceptable salts, enaritiomers and racemates have the advantage that they are inhibitors of the enzyme nitric oxide synthase (NOS): In particular, the compounds of formula (I) and their pharmaceutically acceptable salts, enantiomers and racemates have the advantage that they are inhibitors of the inducible isofomn of the enzyme nitric oxide synthase (iNOS).
The invention further provides a process for the preparation of compounds of formula (I) or a pharmaceutically acceptable salt, enantiomer or racemate thereof.
According to the invention there is also provided a compound of formula (I), or a Zo pharmaceutically acceptable salt, enantiomer or racemate thereof, for use as a medicament.
Another aspect of the invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt, enantiomer or racemate thereof, in the manufacture of a medicament, for the treatment or prophylaxis of diseases or conditions in which inhibition is of nitric oxide synthase activity is beneficial.
A more particular aspect of the invention provides the use of a compound.of formula (I) or a pharmaceutically acceptable salt, enantiomer or racemate thereof, in the manufacture of a medicament, for the treatment or prophylaxis of inflammatory disease.

According to the invention, there is also provided a method of treating, or reducing the risk of, diseases or conditions in which inhibition of nitric oxide synthase activity is beneficial which comprises administering to a person suffering from or at risk of, said disease or condition, a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, enantiomer or racemate thereof.
More particularly, there is also provided a method of treating, or reducing the risk of, inflammatory disease in a person.suffering from or at risk of, said disease, wherein the method comprises administering to the person a therapeutically effective amount of a ~o compound of fomula (I) or a pharmaceutically acceptable salt, enantiomer or racemate thereof.
The compounds of the present-invention may also be used advantageously in combination with a second pharmaceutically active substance; particularly in combination with a is cyclooxygenase inhibitor; more particularly .in combination with a selective inhibitor of the inducible isoform of cyclooxygenase (COX-2). Thus, in a further aspect of the invention there is provided the use of a compound of formula (I) or a pharmaceutically acceptable salt, enantiomer or racemate thereof, in combination with a COX-2 inhibitor for the treatment of inflammation, inflammatory disease and inflammatory related disorders. And zo there is also provided a method of treating,.or reducing the risk of, inflammation, inflammatory disease and inflammatory related disorders in a person suffering from or at risk of, said disease or condition, wherein the method comprises administering to the person a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, enantiomer or racemate thereof in combination with a zs COX-2 inhibitor.
In one embodiment, V represents S(O)n and n represents 0.
In another embodiment, V represents O.

In another embodiment, X and Y independently represent Br, Cl, CH3, CH2F, CHF2, CF3, OCH3 or CN. In yet another embodiment Y represents CN.
In one embodiment, R1 represents H.
s In another embodiment, R2 represents phenyl or a five or six membered aromatic heterocyclic ring containing 1 to 3 heteroatoms independently selected from O, S and N. In a further embodiment, R2 represents phenyl, pyridyl, isoxazolyl, isothiazolyl or thiazolyl.
In a yet further embodiment, R2 represents phenyl.
io In one embodiment, R3 represents H.
In another embodiment R4, RS and R6 each represent H.
is In another embodiment, T, U and W independently represent N, CH or CF. In another embodiment U represents N or CH. In yet another embodiment W represents N or CH.
In one embodiment, each of T, U and W represents CR7.
2o In one embodiment, one of T, U and W represents N and the other two represent CR7.
In a particular embodiment, the compounds of formula (I) have the (1R, 3S) absolute stereochemistry.
is In one particular aspect the invention relates to compounds of formula (I) wherein V
represents O or S; X and Y independently represent Br, Cl, CH3, CH2F, CHF2, CF3, OCH3 or CN; RI, R3, R4, RS and R6 each represent H; R2 represents phenyl, pyridyl, isoxazolyl, isothiazolyl or thiazolyl; T represents N, CH or CF; U represents N or CH; W

represents N or CH; and the compounds have the (1R, 3S) absolute configuration; and pharmaceutically acceptable salts thereof.
In another particular aspect the invention relates to compounds of formula (I) wherein V
represents O or S; X and Y independently represent Br, Cl, CH3, CH2F, CHF2, CF3, OCH3 or CN; R1, R3, R4, RS and R6 each represent H; R2 represents phenyl, pyridyl, isoxazolyl, isothiazolyl or thiazolyl; one of T, U and W represents N and the other two represent CR7; and the compounds have the ( 1 R, 3 S) absolute configuration;
and pharmaceutically acceptable salts thereof.
~o Particular compounds of the invention include:
2-[[( 1 R,3S~-3-amino-4-hydroxy-1-phenylbutyl]thio]-6-methyl-3-pyridinecarbonitrile;
2-[[(3 S)-3-amino-4-hydroxy-1-(3-isoxazolyl)butyl]thio]-6-methyl-3-pyridinecarbonitrile;
4-[[( 1 R,3S)-3-amino-4-hydroxy-1-phenylbutyl]thio]-6-methyl-3-pyridinecarbonitrile;
is 3-[[(1R,3S)-3-amino-4-hydroxy-1-phenylbutyl]thio]-5-(trifluoromethyl)-2-pyridinecarbonitrile;
2-[[( 1 R,3 S)-3-amino-4-hydroxy-1-phenylbutyl]thio]-6-(difluoromethyl)-3-pyridinecarbonitrile; _ 2-[[( 1R,3,S~-3-amino-4-hydroxy-1-phenylbutyl]thin]-6-(fluoromethyl)-3-zo pyridinecarbonitrile;
2-[[( 1 R,3,S~-3-amino-4-hydroxy-1-(3-pyridinyl)butyl]oxy]-4-chloro-5-fluorobenzonitrile;
2-[[( 1 R,3 S)-3-amino-4-hydroxy-1-(2-thiazolyl)butyl]oxy]-4-chloro-5-fluorobenzonitrile;
2-[[( 1 R,3S~-3-amino-4-hydroxy-1-(5-isothiazolyl)butyl]oxy]-4-chloro-5-fluorobenzonitrile;
is 4-[[(1R,3S~-3-amino-4-hydroxy-1-phenylbutyl]thio]-6-methoxy-3-pyridinecarbonitrile;
4-[[( 1 R,3R)-3-amino-4-hydroxy-1-phenylbutyl]thio]-6-methoxy-3-pyridinecarbonitrile;
4-[[( 1 S,3R)-3-amino-4-hydroxy-1-phenylbutyl]thio]-6-methoxy-3-pyridinecarbonitrile;
4-[[( 1 S,3 S)-3-amino-4-hydroxy-1-phenylbutyl]thio]-6-methoxy-3-pyridinecarbonitrile;
4-[ [( 1 R,3 S)-3-amino-4-hydroxy-1-phenylbutyl]thio]-6-(difluoromethoxy)-30 3-pyridinecarbonitrile;

2-[[( 1 R,3R)-3-amino-4-hydroxy-1-phenylbutyl]thio]-6-methyl-3-pyridinecarbonitrile;
4-[[( 1 R,3,S'~-3-amino-4-hydroxy-1-phenylbutyl]thio]-6-(2H3)methoxy-3-pyridinecarbonitrile;
2-[[( 1 R,3 S)-3-amino-4-hydroxy-1-phenylbutyl]thio]-6-ethyl-3-pyridinecarbonitrile;
2-[[( 1 R,3 S)-3-amino-4-hydroxy-1-phenylbutyl]thio]-6-( 1-methylethyl)-3-pyridinecarbonitrile;
2-[[( 1 R,3 S)-3-amino-4-hydroxy-1-phenylbutyl]thio]-6-methyl-3-pyridinemethanol;
6-acetyl-2-[[( 1 R,3 S)-3-amino-4-hydroxy-1-phenylbutyl]thio]-3-pyridinecarbonitrile;
2-[[( 1 R,3 S)-3-amino-4-hydroxy-1-phenylbutyl]thio]-6-(hydroxymethyl)-3-lo pyridinecarbonitrile;
2-[[(1R, 3S)-3-amino-4-hydroxy-1-phenylbutyl]thio]-3-pyridinecarbonitrile;
((315,81R)-(3-amino-8-[(2,5-dichloro-4-pyridinyl)thiobenzenebutanol];
2-[[( 1 R,3 S)-3-amino-4-hydroxy-1-phenylbutyl]thio]-5-fluoro-6-methoxy-3-pyridinecarbonitrile;
is 4-[[(1R,3S)-3-amino-4-hydroxy-1-phenylbutyl]thio]-6-(dimethylamino)-3-pyridinecarbonitrile;
4-[[( 1 R,3 S)-3-amino-4-hydroxy-1-phenylbutyl]thio]-6-(methylamino)-3-pyridinecarbonitrile;
((315,81 R)-[i-amino-8-[(5-bromo-2-methoxy-4-pyridinyl)thio]-benzenebutano1;
zo ((31S,S'R)-(3-amino-8-[(5-chloro-2-methoxy-4-pyridinyl)thio]-benzenebutanol;
4-[[(1R,3S)-3-amino-4-hydroxy-1-phenylbutyl]thio]-6-ethoxy-3-pyridinecarbonitrile;
3-[[( 1R,3S)-3-amino-4-hydroxy-1-phenylbutyl]thin]-5-(trifluoromethyl)-2-pyridinecarbonitrile;
3-[[( 1 R,3 S)-3-amino-4-hydroxy-1-phenylbutyl]thio]-1,6-dihydro-5-methyl-6-oxo-2-zs pyridinecarbonitrile; , 3-[[( 1 R,3 S)-3.-amino-4-hydroxy-1-phenylbutyl]thio]-5-chloro-2-pyridinecarbonitrile;
6-amino-4-[[( 1 R,3 S)-3-amino-4-hydroxy-1-phenylbutyl]thio]-3-pyridinecarbonitrile;
3-[[( 1 R,3 S)-3-amino-4-hydroxy-1-phenylbutyl]thio]-S-methyl-2-pyridinecarbonitrile;
4-[ [( 1 R,3 S)-3-amino-1-(2-fluorophenyl)-4-hydroxybutyl]thio]-6-methoxy-3-3o pyridinecarbonitrile;

2-[[( 1 R,3 S)-3-amino-1-(4-fluorophenyl)-4-hydroxybutyl]oxy]-6-trifluoromethyl-3-pyridinecarbonitrile; -2(2S)-amino-4 (4R)-(3-fluorophenyl)-4-[(4-methoxy-2-nitrophenyl)thio]butan-1-ol;
2(2S)-amino-4(4R)-(3-fluorophenyl)-4-[(4-chloro-2-nitrophenyl)thio]butan-1-ol;
s 2(2S)-amino-4(4R)-(3-fluorophenyl)-4-[(5-amino-4-chloro-2-nitrophenyl)thio]butan-1-ol;
2(2S)-amino-4(4R)-(3-fluorophenyl)-4-[(4-hydroxymethyl)-2-nitrophenyl)thio]butan-1-ol;
2(2S)-amino-4(4R)-(3-fluorophenyl)-4-[(4-fluoro-2-nitrophenyl)thio]butan-1-ol;
2(2S)-amino-4(4R)-(3-fluorophenyl)-4-[(3,5-dichloro-2-pyridyl)thio]butan-1-ol;
4-[[( 1 R,3 S)-3-amino-4-hydroxy-1-phenylbutyl]thio]-3-chlorobenzonitrile;
~0 4-chloro-2-[[(1R,3S)-3-(ethylamino)-4-hydroxy-1-(2-thiazolyl)butyl]oxy]-5-fluoro-benzonitril e;
2-[[( 1 R,3 S)-3-amino-4-hydroxy-1-(5-thiazolyl)butyl]oxy]-5-fluoro-benzonitrile;
2-[ [( 1 R,3 S)-3-amino-4-methoxy-1-phenylbutyl] thio]-6-methyl-3-pyridinecarbonitrile;
2-[ [( 1 R,3 S)-3-amino-4-hydroxy-4-methyl-1-phenylpentyl] oxy]-4-chloro-5-fluoro is benzonitrile;
2-[[( 1 S,3 S)-3-amino-4-hydroxy-1-propylbutyl]oxy]-4-chloro-5-fluorobenzonitrile;
2-[[( 1 S)-1-[(2S)-2-amino-3-hydroxypropyl]pentyl]thio]-6-methyl-3-pyridinecarbonitrile;
2-[[( 1 S,3 S)-3-amino-4-hydroxy-1-(2-methylpropyl)butyl]thio]-6-methyl-3-pyridinecarbonitrile;
20 2-[[(3S)-3-amino-4-hydroxy-1-(5-isoxazolyl)butyl]thio]-6-methyl-3-pyridinecarbonitrile;
2-[[(3S)-3-amino-4-hydroxy-1-(5-isoxazolyl)butyl]oxy]-6-(trifluoromethyl)-3-pyridinecarbonitrile;
2-[ [3-(3 S)-amino-4-hydroxy-1-( 1 R)-(2-thienyl)butyl]oxy]-4-chloro-5-fluorobenzonitrile;
2-[[3-(3 S)-amino-4-hydroxy-1 ( 1 R)-(3-thienyl)butyl]oxy]-4-chloro-5-fluorobenzonitrile;
zs 2-[[(1R,3S)-3-amino-4-hydroxy-1-(3-pyridinyl)butyl]thio]-4-(trifluoromethyl)benzonitrile;
2-[ [( 1 R,3 S)-3-amino-4-hydroxy-1-(5-pyrimidyl)butyl]thio]-4-chlorobenzonitrile;
2-[[( 1 R,3S)-3-amino-4-hydroxy-1-(3-pyridinyl)butyl]thio]-4-chloro-5-fluorobenzonitrile;
2-[ [( 1 R,3 S)-3-amino-4-hydroxy-1-(3~-pyridyl)butyl]thio]-4-bromobenzonitri1e;
2-[ [( 1 R,3 S)-3-amino-4-hydroxy-1-(2-thiazolyl)butyl]oxy]-5-fluoro-6-methyl-3o pyridinecarbonitrile;

4-[ [( 1 R,3 S)-3-amino-1-(3-fluoro-2-thienyl)-4-hydroxybutyl] thin]-6-methoxy-pyridinecarbonitrile;
2-[ [( 1 R,3 S)-3-amino-1-(4-chloro-5-thiazolyl)-4-hydroxybutyl]oxy]-4-chloro-fluorobenzonitrile;
2-[[( 1 R,3 S)-3-amino-4-hydroxy-1-phenylbutyl]thio]-5-nitrobenzonitrile;
2-[[( 1 R,3 S)-3-amino-4-hydroxy-1-phenylbutyl]thio]-5-chloro-3-pyridinecarbonitrile;
(3-amino-8-[(4-amino-2-nitrophenyl)thio]-((3' 5,81 R)-benzenebutanol;
2-[ [( 1 R,3 S)-3-amino-4-hydroxy-1-phenylbutyl] thio]-5-bromo-benzonitrile;
and pharmaceutically acceptable salts, enantiomers or racemates thereof.
io Unless otherwise indicated, the term "C 1 to 4 alkyl" referred to herein denotes a straight or branched chain alkyl group having from 1 to 4 carbon atoms. Examples of such groups.
include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl and t-butyl.
is Unless otherwise indicated, the term "C3 to 6 cycloalkyl" referred to herein denotes a cycloalkyl group having from 3 to 6 carbon atoms. Examples of such groups include cyclopropyl, cyclopentyl and cyclohexyl.
Unless otherwise indicated, the term "C2 to 4 alkenyl" referred to herein denotes a straight zo or branched chain alkyl group having from 2 to 4 carbon atoms incorporating at least one carbon-carbon double bond. Examples of such groups include ethenyl, propenyl and butenyl.
Unless otherwise indicated, the term "C2 to 4 alkynyl" referred to herein denotes a straight zs or branched chain alkyl group having from 2 to 4 carbon atoms incorporating at least one carbon-carbon triple bond. Examples of such groups include ethynyl, propynyl, and butynyl.
Unless otherwise indicated, the term "C 1 to 4 alkoxy" referred to herein denotes a straight 30 or branched chain alkoxy group having from 1 to 4 carbon atoms. Examples of such groups include methoxy, ethoxy, n-propoxy, i-propoxy and t-butoxy.

The term "C 1 to 4 alkylthio" is to be interpreted analogously.
Unless otherwise indicated, the term "halogen" referred to herein denotes fluoro, chloro, bromo and iodo.
s Examples of a 4 to 8 membered saturated azacyclic ring optionally incorporating one further heteroatom selected from O, S or N include pyrrolidine, piperidine, piperazine, niorpholine and perhydroazepine.
io Examples of a 4 to 8 membered saturated heterocyclic ring incorporating one heteroatom selected from O, S or N include pyrrolidine, piperidine, tetrahydrofuran and perhydroazepine.
Examples of a five or six membered aromatic heterocyclic ring containing 1 to ~s heteroatoms independently selected from O, S and N include furan, thiophene, pyridine, thiazole, imidazole, oxazole, triazole, oxadiazole, thiadiazole and pyrimidine.
Examples of a five or six membered saturated heterocyclic ring containing 1 to heteroatoms independently selected from O, S and N include pyrrolidine, tetrahydrofuran, 2o piperidine and piperazine.
Examples of a "C 1 to 4 alkyl or C 1 to 4 alkoxy optionally further substituted by one or more fluorine atoms" include CH2F, CHF2, CF3, CF3CF2, CF3CH2, CH2FCH2, CH3CF2, CF3CH2CH2, OCF3 and OCH2CF3.
2s According to the invention, we further provide a process for the preparation of compounds of formula (I), or a pharmaceutically acceptable salt, enantiomer or racemate thereof which comprises:
30 (a) reaction of a compound of formula (II) X
T' \ W
U / (II) ~L~
Y
wherein T, U, X, Y and W are as defined in formula (I) and L 1 represents a leaving group, with a compound of formula (III) R5 O.R~
R2 Ra (III) s wherein R1, R2, R3, R4, R5, R6 and V are as defined in formula (I); or (b) reaction of a compound of formula (IV) io X
T~W
U / (IV) ~VH
Y
wherein T, U, W, X, Y and V are as defined in formula (I), with a compound of formula (V) R5 O~R1 R2 Ra (V) is wherein R1, R2, R3, R4, RS and R6 are as, defined in formula (I) and L2 is a leaving group;
and where desired or necessary converting the resultant compound of formula (I), or another salt thereof, into a pharmaceutically acceptable salt thereof; or converting one compound of formula (I) into another compound of formula (I); and where desired converting the resultant compound of formula (I) into an optical isomer thereof.
In process (a), the reaction is performed by treating a nucleophile of formula (III) with an electrophile of formula (II) in an inert solvent. Suitable leaving groups L 1 include to sulphonates and halides, particularly fluoride or chloride. The reaction is generally performed in the presence of a non-nucleophilic base such as sodium hydride or caesium carbonate. Suitable organic solvents are those such as N,N-dimethylformamide, N-methyl-2-pyrrolidinone, tetrahydrofuran, acetonitrile and dimethylsulfoxide.
The reaction is generally conducted at a temperature between 0 °C and the boiling point of the is solvent.
In process (b), the reactants (IV) and (V) are coupled together in a suitable inert solvent such as tetrahydrofuran using, for example, Mitsunobu conditions. Thus, for example, the 2o reactants are treated with a phosphine derivative and an azo derivative at a suitable temperature, generally between 0 °C and the boiling point of the solvent. Suitable phosphine derivatives include triphenylphosphine and tributylphosphine.
Suitable azo derivatives include diethyl azodicarboxylate, diisopropyl azodicarboxylate and l,1'-(azodicarbonyl)dipiperidine. Suitable leaving groups L2 include hydroxy.
Alternatively in process (b), the reaction is performed by treating a nucleophile of formula (IV) with an electrophile of formula (V) in an inert solvent. Suitable leaving groups LZ
include sulphonates and halides, particularly chloride or bromide. The reaction is generally performed in the presence of a non-nucleophilic base such as sodium hydride or 3o caesium carbonate. Suitable organic solvents are those such as N,N-dimethylformamide, N-methyl-2-pyrrolidinone, tetrahydrofuran and dimethylsulfoxide. The reaction is generally conducted at a temperature between 0 °C and the boiling point of the solvent.
It will be apparent to a person skilled in the art that in the above processes it may be desirable or necessary to protect an amine or hydroxyl or other potentially reactive group.
Suitable protecting groups and details of processes for adding and removing such groups may be found by reference to the standard text "Protective Groups in Organic Synthesis", 3rd Edition ( 1999) by Greene and Wuts.
io In one preferred embodiment, amine groups are protected as carbamate derivatives, for example, as t-butyloxycarbamates.
In another particularly preferred embodiment, the amine and hydroxyl groups of compounds wherein R1 represents hydrogen are protected simultaneously as a cyclic carbamate, such as is in formula (VI), or as a cyclic hemi-aminal as in formula (VII).
X R R4 X R Ra T' \_ W R2 G T' \ W ~ R2 G
U / ~O U /
V N V N

(VI) (VII) Specific examples of the use of protecting groups are given in the Examples section.
The present invention includes compounds of formula (I) in the form of salts, in particular acid addition salts. Suitable salts include those formed with both organic and inorganic acids. Such acid addition salts will normally be pharmaceutically acceptable although salts of non-pharmaceutically acceptable acids may be of utility in the preparation and 2s purification of the compound in question. Thus, preferred salts include those formed from hydrochloric, hydrobromic, sulphuric, phosphoric, citric, tartaric, lactic, pyruvic, acetic, succinic, fumaric, malefic, methanesulphonic and benzenesulphonic acids.
Salts of compounds of formula (I) may be formed by reacting the free base, or a salt, s enantiomer or racemate thereof, with one or more equivalents of the appropriate acid. The reaction may be carried out in a solvent or medium in which the salt is insoluble or in a solvent in which the salt is soluble, for example, water, dioxane, ethanol, tetrahydrofuran or diethyl ether, or, a mixture of solvents, which may be removed in vacuo or by freeze drying.
The reaction may also be'a metathetical process or it may be carried out on an ion exchange io resin.
Certain novel intermediates of formulae (III), (V), (VI) and (VII) form another aspect of the invention.
~s Compounds of formula (III) may be prepared by reaction of a compound of formula (VIII) R5 O, R' H Ra (VIII) wherein Ri, R3, R4, RS and R6 are as defined in formula (I), zo with an organometallic derivative, R2- M, wherein R2 is as defined in formula (I) and M
represents a metallic residue such as lithium or magnesium-halide. The resulting compound of formula (III) wherein V represents oxygen may then be subsequently converted into compounds of formula (III) wherein V represents sulphur.
is Alternatively, compounds of formula (III) may be prepared by reaction of an amide of fomula (IX) O R~
O Ra (IX) Me-N R6 NH

Me wherein R1, R3, R4, RS and R6 are as defined in fomula (I), with an organometallic derivative, R2- M, wherein R2 is as defined in formula (I) and M
represents a metallic residue such as lithium or magnesium-halide, followed by reduction of the resulting ketone to the corresponding alcohol (III).
Compounds of formulae (II), (IV), (VIII) and (IX) are either known or may be prepared by conventional methods that will be readily apparent to the man skilled in the art.
~o Intermediate compounds may be used as such or in protected form. Protecting groups and details of processes for their removal may be found by reference to the standard text "Protective Groups in Organic Synthesis", 3rd Edition (1999) by Greene and Wuts.
~ s The compounds of the invention and intermediates thereto may be isolated from their reaction mixtures and, if necessary further purified, by using standard techniques.
The compounds of formula I may exist in enantiomeric fornzs. Therefore, all enantiomers, diastereomers, racemates and mixtures thereof are included within the scope of the invention.
2o The various optical isomers may be isolated by separation of a racemic mixture of the compounds using conventional techniques, for example, fractional crystallisation, or HPLC.
Intermediate compounds may also exist in enantiomeric forms and may be used as purified enantiomers, diastereomers, racemates or mixtures.
zs The compounds of formula (I), and their pharmaceutically acceptable salts, enantiomers and racemates, are useful .because they possess pharmacological activity in animals. In particular, the compounds are active as inhibitors of the enzyme nitric oxide synthase.
More particularly, they are inhibitors of the inducible isoform of the enzyme nitric oxide synthase and as such are predicted to be useful in therapy, for example, as anti-inflammatory agents. They may also have utility as inhibitors of the neuronal isoform of the enzyme nitric oxide synthase.
The compounds and their pharmaceutically acceptable salts, enantiomers and racemates are indicated for use in the treatment or prophylaxis of diseases or conditions in which synthesis or oversynthesis of nitric oxide synthase forms a contributory part. In particular, the compounds are indicated for use in the treatment of inflammatory conditions in mammals io including man.
Conditions that may be specifically mentioned are:
osteoarthritis, rheumatoid arthritis, rheumatoid spondylitis, gouty arthritis and other arthritic conditions, inflamed joints;
is eczema, psoriasis, dermatitis or other inflammatory skin conditions such as sunburn;
inflammatory eye conditions including uveitis, glaucoma and conjunctivitis;
lung disorders in which inflammation is involved, for example, asthma, bronchitis, chronic obstructive pulmonary disease, pigeon fancier's disease, farmer's lung, acute respiratory distress syndrome;
2o bacteraemia, endotoxaemia (septic shock), aphthous ulcers, gingivitis, pyresis, pain, meningitis and pancreatitis;
conditions of the gastrointestinal tract including inflammatory bowel disease, Crohn's disease, atrophic gastritis, gastritis varialoforme, ulcerative colitis, coeliac disease, regional ileitis, peptic ulceration, irntable bowel syndrome, reflux oesophagitis, damage to the is gastrointestinal tract resulting from infections by, for example, Helicobacter pylori, or from treatments with non-steroidal anti-inflammatory drugs;
and other conditions associated with inflammation.
The compounds will also be useful in the treatment and alleviation of acute pain or persistent 3o inflammatory pain or neuropathic pain or pain of a central origin.

We are particularly interested in the conditions inflammatory bowel disease, rheumatoid arthritis, osteoaithritis, chronic obstructive pulmonary disease and pain.
The compounds of formula (I) and their pharmaceutically acceptable salts, enantiomers and s racemates may also be useful in the treatment or prophylaxis of diseases or conditions in addition to those mentioned above. For example, the compounds may be useful in the treatment of atherosclerosis, cystic fibrosis, hypotension associated with septic and/or toxic shock, in the treatment of dysfunction of the immune system, as an adjuvant to short-term immunosuppression in organ transplant therapy, in the control of onset of diabetes, in the ~o maintenance of pancreatic function in diabetes, in the treatment of vascular complications associated with diabetes 'and in co-therapy with cytokines, for example TNF or interleukins.
The compounds of formula (I) may also be useful in the treatment of hypoxia, for example in cases of cardiac arrest and stroke, neurodegenerative disorders including nerve degeneration is and/or nerve necrosis in disorders such as ischaemia, hypoxia, hypoglycaemia, epilepsy, and in external wounds (such as spinal cord and head injury), hyperbaric oxygen convulsions and toxicity, dementia, for example pre-senile dementia, Alzheimer's disease and AIDS-related dementia, Sydenham's chorea, Parkinson's disease, Tourette's syndrome, Huntington's disease, amyotrophic lateral sclerosis, multiple sclerosis, muscular dystrophy, Korsakoffs disease, zo imbecility relating to a cerebral vessel disorder, sleeping disorders, schizophrenia, depression, pain, autism, seasonal affective disorder, jet-lag, depression or other symptoms associated with premenstrual syndrome (PMS), anxiety and septic shock. Compounds of formula (I) may also be expected to show activity in the prevention and reversal of drug addiction or tolerance such as tolerance to opiates and diazepines, treatment of drug addiction, treatment of zs migraine and other vascular headaches, neurogenic inflammation, in the treatment of , gastrointestinal motility disorders, cancer and in the induction of labour.
We are particularly interested in the conditions stroke, Alzheimer's disease, Parkinson's disease, multiple sclerosis, schizophrenia, migraine, cancer, septic shock and pain.
Prophylaxis is expected to be particularly relevant to the treatment of persons who have suffered a previous episode of, or are otherwise considered to be at increased risk of, the disease or condition in question. Persons at risk of developing a particular disease or condition generally include those having a family history of the disease or condition, or those who have been identified by genetic testing or screening to be particularly susceptible to developing the disease or condition.
For the above mentioned therapeutic indications, the dosage administered will, of course, vary with the compound employed, the mode of administration and the treatment desired.
However, in general, satisfactory results are obtained when the compounds are administered at a dosage of the solid form of between 1 mg and 2000 mg per day.
io The compounds of formula (I), and pharmaceutically acceptable derivatives thereof, may be used on their own, or in the form of appropriate pharmaceutical compositions in which the compound or derivative is in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier. Administration may be by, but is not limited to, enteral (including oral, ~s sublingual or rectal), intranasal, inhalation, intravenous, topical or other parenteral routes.
Conventional procedures for the selection and preparation of suitable pharmaceutical formulations are described in, for example, "Pharmaceuticals - The Science of Dosage Form Designs", M. E. Aulton, Churchill Livingstone, 1988. The pharmaceutical composition preferably comprises less than 80% and more preferably less than 50% of a zo compound of formula (I), or a pharmaceutically acceptable salt, enantiomer or racemate thereof.
According to the invention, we further provide a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt, enantiomer or racemate zs thereof, in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier.
There is also provided a process for the preparation of such a pharmaceutical composition which comprises mixing the ingredients.
3o The compounds of fomula (I), and pharniaceutically acceptable derivatives thereof, may also be advantageously used in combination with a COX inhibitor, more particularly in combination with a COX-2 inhibitor. Particularly preferred COX-2 inhibitors are Celecoxib and MK-966. The NOS inhibitor and the COX-2 inhibitor may either be formulated together within the same pharmaceutical composition for administration in a single dosage unit, or each component may be individually formulated such that separate dosages may be administered either simultaneously or sequentially.
s The invention is illustrated, but in no way limited, by the following examples:
The following abbreviations are used:- DMSO (dimethylsulfoxide), DMF (N,N
dimethylformamide), THF (tetrahydrofuran), NMP (N methylpyrrolidinone).
io Example 1 2-f f ( 1R,3S)-3-Amino-4-hydroxv-1-phenylbutyllthiol-6-methyl-3-pyridinecarbonitrile ethanedioate a) 1,1-Dimethylethyl (4S)-4-f(2S)-2-hydroxy-2-phen~hyll-2,2-dimethyl-3-i s oxazolidinecarboxylate and 1,1-Dimeth~hy~4S)-4-f (2R)-2-hydrox~-phen 1y ethyll-2,2-dimethyl-3-oxazolidinecarbox To a stirred solution of 1,1-dimethylethyl (4S)-2,2-dimethyl-4-(2-oxoethyl)-3-oxazolidinecarboxylate (6.9 g) in dry THF ( 100 ml) at 0 °C and under nitrogen, was added phenyl magnesium bromide (34 ml, 1 M in THF). During the addition an exotherm to 20 zo °C occurred, and the mixture was kept at this temperature for 3 h.
The reaction mixture was quenched with 5% aqueous citric acid (100 ml) and the products extracted into ethyl acetate (150 ml). The organic extract was dried (MgS04) and concentrated to an oil. The crude mixture of diastereomers was purified by chromatography (silica, 10%
diethyl ~ether/isohexane as eluent) to give the (4S, 2S) sub-title compound (3.5 g, 38%) as a zs colourless solid .
1H NMR 400MHz (CDCl3) 7.4-7.2 (5H, m), 4.88 (1H, d), 4.65 (1H, m), 4.35 (1H, m), 4.0 (.l H, m), 3.65 ( 1 H, d), 2.1-2 ( 1 H, m), 1.85-1.95 ( 1 H, rri), 1.6 (3H, s), 1.49 ( 12H, s).

Further elution gave the (4S, 2R) sub-title compound (2.5 g, 27%) as a colourless solid.
~H NMR 400MHz (CDC13) 7.4-7.3 (5H, brs), 4.77-4.73 (1H, m), 4.3-3.7 (3H, m), 2.2-2 (2H, m), 1.6-1.4 (15H, m).
s b) 1,1-Dimethylethyl (4S) 4-f (2R)-2-(benzoylthio)-2-phen ly~ethyll-2,2-dimethyl-3-oxazolidinecarbox~ate To a solution of the (4S, 2S) product from step (a) (3 g) and tris(4-chlorophenyl)phosphine in dry THF at 0 °C was added diisopropylazodicarboxylate ( 1.84 ml) dropwise over 5 io minutes. After the addition was complete the mixture was stirred for 20 minutes and then thiobenzoic acid ( 1.1 ml) added. The cooling bath was removed and stirnng continued overnight. The mixture was concentrated and the residue was purified by chromatography (silica, 10% diethyl ether/isohexane as eluent) to give the sub-title compound (1.2 g, 29%) as a yellow coloured solid.
is MS APCI +ve m/z 342 ([M+H-Boc]+).
c) 1,1-Dimethylethyl (4S) 4-[~2R)-2-f 3-cyano-6-methyl-2-pyridinyl)thiol-2-phenyleth 2,2-dimethyl-3-oxazolidinecarbox~ , 2o A mixture of the product from step (b) (4.40 mg), 2-chloro-6-methyl-3-pyridinecarbonitrile (229 mg), sodium carbonate ( 1 S 9 mg) and water ( 1 ml) in methanol ( 10 ml) was stirred at room temperature for 17 h. The mixture was diluted with water (SOmI) and extracted with diethyl ether (2 x 50 ml). The combined extracts were dried (MgS04) and concentrated to an oil and purified by chromatography (silica, 10% diethyl ether/isohexane as eluent) to zs afford the protected amino alcohol.
MS APCI +ve m/z 454 [M+H]+.
d) 2-ff(1R 3S)-3-Amino-4-h~drox~phen l~yllthiol-6-methyl-3-pyridinecarbonitrile 3o ethanedioate The total product from step (c) was dissolved in ethylene glycol (2 ml), a crystal of pyridinium tosylate added and the solution heated at 190 °C for 10 minutes. The mixture was cooled to ambient temperature, diluted with methanol (50 ml), and the solution stirred with SCX resin. The resin was collected by filtration and treated with methanolic s ammonia. The ammonia solution was concentrated to dryness and the residue purified by chromatography (silica, 10% 7M methanolic ammonia in dichloromethane as eluent) to afford the free base (70 mg, 22%). The amine was converted into the ethanedioate salt using one equivalent of oxalic acid in ethanol to afford the title compound.
io MS APCI +ve '°/z 314 [M+H]+.
1H NMR 400MHz (d6-DMSO) 8.1-7.2 (7H, m), 5.33 (1H, t), 3.6-3.4 (2H, m), 2.93 (1H, br m), 2.59 (3H, s), 2.35-2.2 (2H, m).
Example 2 ~s 2-[[(3 S)-3-Amino-4-hydroxy-1-(3-isoxazolyl)butYllthiol-6-methyl-3-pyridinecarbonitrile ethanedioate a) (4S)-4-~2-(3-Isoxazolyl)-2-oxoethvll-2-oxazolidinone zo Dibromoetharie (0.4 g) was added to a suspension of zinc dust ( 1.3 g) iri dry THF (4 ml) under nitrogen, and the mixture heated to ca. 60 °C. After immediately cooling to room temperature, further dibromoethane (0.4 g) was added and the heat / cool cycle was repeated. THF (5 ml) and chlorotrimethylsilane (0.2 ml) W ere added and the mixture stirred for 2 minutes. A solution of (4R)-4-(iodomethyl)-2-oxazolidinone (2.26 g) in THF
2s (4 ml) was added dropwise (a slight exotherm was observed) and the reaction heated at 30 °C for 1 h. After cooling to room temperature, THF (6 ml) was added and the suspension was left to stand for 1 h. The supernatant was transferred by cannula over 5 minutes into a solution of lithium chloride (0.84 g) and copper (I) cyanide (0.88 g) in THF
(8 ml) at -78 °C under nitrogen (the salts had previously been stirred together for 10 minutes at room 3o temperature). The mixture was warmed to 0 °C, re-cooled to -78 °C and a solution of 3-isoxazolecarbonyl chloride (0.78 g) in THF (1 ml) added. After 1 h, the mixture was warmed to -10 °C and left to slowly warm to room temperature over 16 h.
The reaction mixture was poured into a mixture of ethyl acetate and saturated ammonium chloride solution and the mixture filtered through celite. The organic layer was then separated and s washed with water and brine and dried (MgS04). The solvent was evaporated and the residue purified by chromatography (silica, 25 to 100% ethyl acetate/isohexane as eluent) to give the sub-title compound (0.82 g, 70%) as an oily solid.
1 H NMR 400MHz (d6-DMSO) 9.15 ( 1 H, s), 7.71 ( 1 H, s), 6.95 ( 1 H, s),, 4.50 ( 1 H, t), 4.26 i o ( 1 H, quintet), 4.03 ( 1 H, dd), 3.44 ( 1 H, dd), 3:30 ( 1 H, m).
b) (4S1-4-f2-H~droxy-2-(3-isoxazolyl)ethyll-2-oxazolidinone Borane (4.16 ml of a 1M solution in THF) was added to a solution of (R)-2-methyl-CBS-oxazaborolidine (0.42 ml, 1 M solution in toluene) in THF (4 ml) at 0 °C. After 10 minutes, is a solution of (4f~-4-[2-(3-isoxazolyl)-2-oxoethyl]-2-oxazolidinone (0.82 g) in THF (3 ml) was added over 5 minutes and the resultant solution was stirred at 0 °C
for 1h and at 20 °C
for 18h. Methanol (25 ml) was added and the mixture was stirred for 15 minutes. The mixture was evaporated, re-dissolved in methanol and re-concentrated in vacuo 2 more times. The residue was purified by chromatography (silica, ethyl acetate as eluent) to give 2o the sub-title compound (0.55 g) as a colourless oil; 1.5:1 mixture of diastereomers by NMR.
1H NMR 400MHz (d6-DMSO) (major diastereomer) 8.27 (1H, s), 7.83 (1H, s), 6.56 (1H, s), 5.70 ( 1 H, d), 4.83 ( 1 H, m), 4.45-4.37 ( 1 H, m), 4.00 (2H, m), 2.01-1.82 (2H, m).
c) (4S)-4~2-~Benzoylthio)-2-(3-isoxazol~)ethyl]-2-oxazolidinone To a solution of triphenylphosphine ( 1.45 g) in THF (30 ml) at 0 °C
under nitrogen was added diisopropylazodicarboxylate (1.15 ml) dropwise. After 45 minutes, a solution of thiobenzoic acid (0.77 g) and the product from step (a) (0.547 g) in THF ( 10 ml) was 3o added dropwise. The reaction was warmed to room temperature and stirred for 16 h. The solvent was evaporated, and the residue purified by chromatography (silica, 2 to 75% ethyl acetate/isohexane as eluent) to give the sub-title compound (1.2 g) (1.5:1 diastereomeric mixture) as an oily solid.
' 1 H NMR 400MHz (d6-DMSO) 8.91 ( 1 H, s), 8.02-7.53 (6H, m), 6.71 ( 1 H, s), 5.08 ( 1 H, s dd), 4.3 3 ( 1 H, t), 4.01 ( 1 H, dd), 3 . 76 ( 1 H, quintet), 2.34 ( 1 H, m), 2.17 ( 1 H, m).
~2-ff 1-(3-Isoxazol l~)-2-[(4S1-2-oxooxazolidinyllethyllthiol-6-methyl-3-pyridinecarbonitrile The product from step (c) (0.6 g) was dissolved in 7M ammonia in methanol (8 ml), stirred io at room temperature under nitrogen for 2 h and then the solvent was evaporated. The residue was dissolved in DMF (5 ml) and a mixture of caesium carbonate (0.85 g) and 2-chloro-6-methyl-3-pyridinecarbonitrile (0.2 g) added. After stirring for 3 h, ethyl acetate and water were added, and the organic layer separated. The aqueous layer was further extracted with ethyl acetate. The combined organic extracts were washed with 1M aqueous is sodium hydroxide solution and brine, then dried (Na2S04). The solvent was evaporated and the residue purified by chromatography (silica, 40 to 80% ethyl acetate/isohexane as eluent) to give the sub-title compound (0.15 g) (3:1 diastereomeric mixture) as an oily solid.
2o 1 H NMR 400MHz (d6-DMSO) 8.92 ( 1 H, d), 8.13 ( 1 H, d), 8.01 ( 1 H, bs), 7.25 ( 1 H, d), 6.74 ( 1 H, d), 5.45 ( 1 H, dd); 4.30 ( 1 H, t), 4.00 ( 1 H, dd), 3.74 ( 1 H, m), 2. S 8 (3H, s), 2.40=2.20 (2H, m).
e) 1 1-Dimethylethyl (4S~-4-[2-f(3-cyano-6-methyl-2-pyridinyl)thiol-2-(3-2s isoxazolyl)ethyl]-2-oxo-3-oxazolidinecarboxylate To a solution of the product from step (d) (0.15 g) in THF (2 ml) were added sequentially triethylamine (0.10 ml), carbonic acid, (l,l-dimethylethoxy)carbonyl 1,1-dimethylethyl ester (0.15 g) and dimethylaminopyridine (13 mg), and the solution was then stirred for 16 h. Diethyl ether and water were added and the organic layer separated. The organic extract 3o was washed with aqueous potassium hydrogensulfate solution and brine, then dried over (NaZS04). The solvent was evaporated and the residue purified by chromatography (silica, 40 to SO% ethyl acetate in isohexane as eluent) to give the sub-title compound (70 mg) as a white solid.
1 H NMR 400MHz (d6-DMSO) (major diastereomer) 8.91 ( 1 H, d), 8.15 ( 1 H, d), 7.27 ( 1 H, s d), 6.74 (1H, d), 5.47 (1H, dd), 4.50-4.30 (3H, m), 2.57 (3H, s), 2.60-2.40 (2H, m), 1.44 (9H, s).
f) l,l-Dimethylethyl f(1ST-3-'~[(3-cyano-6-meth~p~dinyl)thiol-1-(hydrox~yl)-3-(3-isoxazolyl)propyllcarbamate to To a solution of the product from step (e) (70 mg) in methanol (2.4 ml) was added caesium carbonate (0.01 g) and the solution stirred for 3 h. Ethyl acetate and water were added, and the organic layer was separated. The organic extract was washed with brine, dried (Na2S04), evaporated and the residue purified by chromatography (silica, 50 to 60% ethyl acetate/isohexane as eluent) to give the sub-title compound (54 mg) as a white solid.
IS
1 H NMR 400MHz (CDC13) (major diastereomer) 8.38 (1 H, d), 7.72 ( 1 H, d), 7.00 ( 1 H, d), 6.43 ( 1 H, d), 5.42 ( 1 H, d), 5.22 ( 1 H, s), 3.80-3.67 (2H, m), 3.61 ( 1 H, dt), 2.66 (3 H, s), 2.54 (2H, m), 2.20 ( 1 H, m), 1.45 (9H, s).
2o X12-ffl3Sl-3-Amino-4-hvdroxv-1-(3-isoxazolvl)butvllthiol-6-methyl-3-pyridinecarbonitrile ethanedioate The product from step (f) (60 mg) was dissolved in 4M HCl in dioxane (5 ml).
After 2 h, tl~e volatiles were removed, the residue taken up in methanol and passed through a SCX
ion exchange resin eluting with methanol followed by 7M ammonia in methanol.
The 2s solvents were removed to afford the free base of the title product (50 mg).
This material was taken up in acetonitrile (3 ml) and methanol (1 ml) and a solution of oxalic acid (14 mg) in diethyl ether added. The solvents were removed, ethyl acetate added, and the crystals filtered off and dried to give the title compound (30 mg) as a cream solid as an 80:20 (1R):(1S~ diastereomeric mixture.
MS APCI +ve n'/z 305 [M+H]+.

1 H NMR 400MHz (d6-DMSO) 8.92 ( 1 H, d), 8.16 ( 1 H, d), 7.99 (ca. 2H, vbs), 7.29 ( 1 H, d), 6.68 (1H, d), 5.55 (1H, t), 3.63 (1H, dd), 3.52 (1H, dd), 3.20 (1H, bs), 2.58 (3H, s), 2.40-2.20 (2H, m).
s Example 3 4-f f ( 1 R.3 S)-3-Amino-4-hydrox~phenylbutyllthiol-6-methyl-3-pyridinecarbonitrile ethanedioate io . al 1.1-Dimethvlethvl (4S1-4-f(2R)-2-f(5-cvano-2-methyl-4-pvridinvl)thiol-2-phenvlethv1l-2,2-dimethyl-3-oxazolidinecarboxylate The product from Example 1 step (b) (406 mg) was treated with 7M ammonia in methanol (30 ml) and stirred at room temperature for 6h.The solvent was evaporated, the residue dissolved in dry DMF (25 ml) and treated with 4-chloro-6-methyl-3-pyridinecarbonitrile is (154 mg) followed by caesium carbonate (600 mg) under nitrogen. The reaction mixture was stirred for 24 h, poured into brine and ethyl acetate and the organic layer separated, washed with water (5 times) and then brine and dried (MgS04).The solvent was evaporated and the residue purified by chromatography (silica, 5% ethyl acetate/dichloromethane as eluent) to give the sub-title compound (177 mg, 42%) as a viscous oil.
zo MS APCI +ve m/z 454 [M+H]+.
b 4-f [( 1 R,3 S)-3-Amino-4-h~ox~l=phenylbutyllthiol-6-methyl-3-pyridinecarbonitrile ethanedioate zs The product from Example 3 step (a) ( 177 mg) was stirred in 4M HCl in dioxane (S ml) and methanol (5 ml) for 1h. The reaction mixture was evaporated, azeotroped with ether (3 times), then treated with 1 equivalent of oxalic acid in ethanol ( 10 ml). The clear solution was treated with ether until complete precipitation and the solid collected by filtration, washed with ether and dried in vacuo at 40 °C for 2 h to give the title compound (76 mg, 30 48%) as a light brown solid.
MS APCI + ve m/z 314 [M+H~+.

1H NMR 300MHz (d6-DMSO) 8.7 (1H, s), 7.54 (3H, m), 7.40 (2H, m), 7.31 (1H, m), 5.15 ( 1 H, t), 3.48 ( 1 H, dd), 3 .3 8 ( 1 H, m), 2.90 ( 1 H, br m), 2.50 (3 H, s), 2.3 0 ( 1 H, m), 2.14 ( I H, m).
s Example 4 3-f f ( 1 R,3S~-3-Amino-4-hydroxy-1-phenylbutyllthiol-5-(trifluoromethyl)-2-wridinecarbonitrile ethanedioate io al 1.1-Dimethvlethvl (4S~-4-f(2R)-2-ff2-cvano-5-(trifluoromethvl)-3-pvridinvllthiol-2-phenylethyll-2,2-dimethyl-3-oxazolidinecarboxylate The product from Example 1 step (b) (411 mg) was stirred in 7M ammonia in methanol (30 ml) for 6 h. The solvent was evaporated, the residue dissolved in dry DMF (25 ml) and treated under nitrogen with stirring with 3-chloro-5-(trifluoromethyl)-2-Is pyridinecarbonitrile (210 mg) followed by caesium carbonate (610 mg). The reaction mixture was stirred under nitrogen overnight at room temperature, poured into brine and ethyl acetate, and the organic layer separated, washed with water (5 times) then brine and dried (MgS04). The solvent was evaporated and the residue purified by chromatography (silica, 5% ethyl acetate/isohexane as eluent) to give the sub-title compound (190 mg, zo 40%) as a viscous oil.
MS APCI +ve m/z 408 [M-Boc +I]+.
b) 3-ff(IR,3,S~-3-Amino-4-hydroxy-1-phenylbutyllthio]I-5-(trifluoromethYl)-2-zs pyridinecarbonitrile ethanedioate The product from Example 4 step a) (190 mg) was stirred in 4 M hydrogen chloride in dioxane (5 ml) and methanol (5 ml) for 1 h. The reaction mixture was evaporated, the residue treated with aqueous sodium bicarbonate and ethyl acetate, and the organic layer separated and dried (MgS04). The solvent was evaporated and the residue treated with an 3o equivalent of oxalic acid in ethanol. The solution was evaporated and the residue treated with acetonitrile and a few drops of ether to precipitate a colourless solid which was collected by filtration, washed with ether and dried to give the title compound (133 mg, 78%).
MS APCI +ve ~/z 368 [M+H]+.
s 1H NMR 300MHz (d6-DMSO) 8.98 (1H, s), 8.33 (1H, s), 7.34 (5H, m), 5.04 (1H, t), 3.58 ( 1 H, dd), 3 .48 ( 1 H, m), 3.05 ( 1 H, m), 2.3 3 ( 1 H, m), 2.18 ( 1 H, m).
Example 5 io 2-ff(1R,3S~-3-Amino-4-hydroxy-1-phenylbutyllthio]-6-(difluoromethyl)-3-pyridinecarbonitrile (~-butenedioate a) 6-(Difluoromethyl)-2-(methylthio)-3-pyridinecarbonitrile To a solution of 6-formyl-2-(methylthio)-3-pyridinecarbonitrile (1 g) in dichloromethane is under nitrogen was added [bis(methoxyethyl)amino]sulfur trifluoride (2 ml) followed by ethanol. (0.05 ml). After 16 h, the reaction mixture was cautiously poured into saturated aqueous sodium bicarbonate solution. The organic layer was separated and the aqueous layer extracted with further dichloromethane. The combined organic layers were dried ((sodium sulphate)) and the solvent removed. Tlie residue was taken up in methanol and 2o passed through a SCX ion exchange resin eluting with methanol. The solvents were removed to afford the title product ( 1.2 g) as a yellow solid.
~H NMR 400MHz (CDC13) 7.93 (1H, d), 7.38 (1H, d), 6.59 (1H, t), 2.65 (3H, s).
Zs b) 6-(Difluoromethyl)-2-(methylsulfon~)-3-pyridinecarbonitrile To a solution of the product from Example 5 step (a) (1.2 g) in dichloromethane (12 ml) at 0 °C was added 3-chloroperoxybenzoic acid (6.8 g of minimum 57%
purity). The reaction was warmed to room temperature and stirred for 2 h. The reaction was, washed with aqueous sodium bicarbonate solution and dried over (NaZS04). The solvent was evaporated 3o and the residue taken up in diethyl ether. The organic solution was washed with aqueous sodium metabisulfite solution, ice cold aqueous 0.5M sodium hydroxide solution, brine, and then dried (NazS04). The solvent was removed to give the sub-title compound (0.58 g) as a pale yellow oil.
1H NMR 400MHz (CDC13) 8.44 (1H, d), 8.03 (1H, d), 6.72 (1H; t), 3.42 (3H, s).
s c) 1,1-Dimethylethyl (4S~-4-f f (2R)-2-f f 3-cyano-6-(difluoromethyl)-2-pyridinyllthiol-2-phenylethyl~-2,2-dimethyl-3-oxazolidinecarboxylate The title compound was prepared by the method of Example 4 step (a) using the product of Example 1 step (b) and 6-(difluoromethyl)-2-(methylsulphonyl)-3-pyridinecarbonitrile io to give, after purification by chromatography (silica, 5% ethyl acetate in isohexane as eluent) the sub-title compound (252mg, 74%) as a viscous oil.
MS APCI +ve m/z 390 [M-Boc +1]+.
is d 2-f[~1R,3,S~-3-Amino-4-hydroxy-1-phenylbutyllthiol-6-(difluorometh~)-3-pyridinecarbonitrile (E)-butenedioate The product from step (c) was deprotected as in Example 4 step (b) and then converted into the (E)-butenedioate salt by addition of one equivalent of fumaric acid to give the title compound (121 mg, 51%) as a colourless foam.
zo MS APCI +ve °'/z 350 [M+H]+.
~H NMR 300MHz (d6-DMSO) 8.40 (1H, d), 7.59 (1H, d), 7.52 (2H, d), 7.31 (3H, m), 7.10 ( 1 H, t), 6.45 (2H, s), 5.35 ( 1 H, q), 3.38 (2H, m), 2.75 ( 1 H, br m), 2.31 ( 1 H, m), 2.18 ( 1 H, m).
zs Example 6 2-[j(1R,3,S~-3-Amino-4-hydroxy-1-phen l~~llthiol-6-(fluoromethyl)-3-Qyridinecarbonitrile (E)-butenedioate a) 6-(Fluoromethyl)-2-.(metl~lthio)-3-pyridinecarbonitrile To a solution of 6-formyl-2-(methylthio)-3-pyridinecarbonitrile (1 g) in ethanol (12 ml) was added sodium borohydride (0.212 g). After 2 h, the volatiles were removed and ethyl acetate and water added. The organic layer was separated and the aqueous layer extracted with further ethyl acetate. The combined organic layers were dried (Na2S04) and the s solvent removed to afford 6-(hydroxymethyl)-2-(methylthio)-3-pyridinecarbonitrile (1 g) as yellow solid. This material was taken up in dichloromethane ( 10 ml) under nitrogen and [bis(methoxyethyl)amino]sulfur trifluoride (1 ml) in dichloromethane (3 ml) was added.
After 16 h the reaction mixture was cautiously poured into saturated aqueous sodium bicarbonate solution. The organic layer was separated, dried (Na2S04) and the solvent to removed. The residue was taken up in methanol and passed through a SCX ion exchange resin eluting with methanol. The solvents were removed to afford the sub-title product (0.88 g) as a yellow solid.
1H NMR 400MHz (CDC13) 7.85 (1H, d), 7.23 (1H, d), 5.48 (2H, d), 2.60 (3H, s).
Is b) 6-(Fluoromethyl)-2-(methylsulfon 1~)-3-pyridinecarbonitrile The title compound was prepared by the method of Example 5 step (b) using the product of Example 6 step (a) and 3-chloroperoxybenzoic acid. The product was obtained as a pale green oil which solidified upon standing.
IH NMR 400MHz (CDC13) 8.33 (1H, d), 7.87 (1H, d), 5.60 (2H, d), 3.37 (3H, s).
c~ l,l-Dimethylethyl (4,5~-4-[[(2R)-2-f13-cyano-6-(fluoromethyl)-2-pyridine]thiol-2-phenylethyll-2,2-dimethyl-3-oxazolidinecarboxylate 2s The title compound was prepared by the method of Example 4 step (a) using the product of Example 1 step (b) and 6-(fluoromethyl)-2-(methylsulphonyl)-3-pyridinecarbonitrile to give, after chromatography (silica, 10 to 30% diethyl ether in isohexane as eluent) the sub-title compound (318 mg) as an off white foam.
3o IH NMR 400MHz (db-DMSO) 8.26 (1H, d), 7.46 (2H, d), 7.35 (3H, m), 7.25 (1H, t), 5.76-5.44 (2H, m), 5.14 (1H, dd), 4.00-3.53 (3H, br m), 2.50-2.00 (2H, m), 1.46-1.36 (15H, m).

d~ 2-'[[(1R,3S)-3-Amino-4-hydroxy-1-phenylbutyllthiol-6-(fluoromethyl)-3-pyridinecarbonitrile (~-butenedioate The product from step (c) was deprotected as in Example 4 step (b) and then converted into the (E~-butenedioate salt by addition of one equivalent of fumaric acid to give the title compound (224 mg) as an off white foam.
MS APCI +ve m/z 332 [M+H]+.
1H NMR 400MHz (CD30D) 8.07 (1H, d), 7.49 (2H, m), 7.38-7.27 (4H, m), 6.68 (2H, s), ~ 0 5.62 ( 1 H, q), 5.49 ( 1 H, t), 3 .69 ( 1 H, dd), 3.5 5 ( 1 H, dd), 3.26 ( 1 H, m), 2.43 ( 1 H, ddd), 2.34 ( 1 H, ddd).
ExamQle 7 is 21j(1R,3,S~-3-Amino-4-h dery-1-(3-wridinyl butylloxyl-4-chloro-5-fluorobenzonitrile Dihydrochloride aJl 1,1-Dimeth 1y eth,~S~-4-f (2R)-2-h~y-2-(3-pyridinyl)ethyl]-2,2-dimethyl- 3-oxazolidinecarboxylate zo The title compound was prepared by the method of Example 1 step (a) to give the more polar diastereomer as a colourless oil.
MS APCI +ve m/z 222 [M+H-Boc]+.
zs b) 1,1-Dimethylethyl (4f~-4-f(2R)-2-(5-chloro-2-cyano-4-fluorophenox )-y 2-(3-pyridinyhleth~l-2,2-dimethyl-3-oxazolidinecarboxylate Sodium hydride (60% in mineral oil) (24 mg) was added cautiously to a stirred solution 9f 4-chloro-2,5-difluorobenzonitrile (90 mg) and the product from step (a) (165 mg) in dry DMF (5 ml) and stirring was continued for 2 h. The reaction mixture was quenched with 3o water, extracted twice with ethyl acetate, the extracts dried (NazS04) and evaporated. The residue was purified by chromatography (silica, 10% ethyl acetate/hexanes as eluent) to give the sub-title compound (220 mg) as a colourless foam.

MS APCI +ve "'/z 376 [M+H-Boc]+.
c) 2-f f (1R,3S~-3-Amino-4-h~ -y 1-(3-Ryridin~)butylloxyl-4-chloro-5-s fluorobenzonitrile dihydrochloride The product from step (b) (220 mg) was stirred with methanol (1 ml) and 4 M
hydrogen chloride in dioxane (2 ml) for 2 h. The reaction mixture was evaporated and triturated with diethyl ether to give the title compound ( 130 mg) as a white solid.
io MS APCI +ve m/z 336 [M+H]+.
' H NMR 400MHz (db-DMSO) 8.95 ( 1 H, s), 8.75 ( 1 H, d), 8.27-8.21 (4H, m), 8.06 ( 1 H, d), 7. 81-7.78 ( 1 H, t), 7.62 ( 1 H, d), 6.23-6.20 ( 1 H, m), 3.72-3 .65 ( 1 H, dd), 3.61-3 .58 ( 1 H, m), 3.3-3.2 ( 1 H, br.s), 2.40-2.31 ( 1 H, m), 2.27-2.20 ( 1 H, m).
is Example 8 2-f f ~1R,3,S~-3-Amino-4-hydroxy-~2-thiazolyl)butylloxv]-4-chloro-5-fluorobenzonitrile ethanedioate Zo a) 1,1-Dimethylethyl LS1-4-[(2f~-2-hydroxy-2-(2-thiazolyl)ethyl]-2,2-dimethyl-3 oxazolidinecarboxvlate and 1,1-Dimethvlethvl (4Sl-4-f (2Rl-2-hvdroxv-2-(2 thiazolyl)ethyl]-2,2-dimethyl-3-oxazolidinecarboxylate To a stirred solution of (4,5~-2,2-dimethyl-4-(2-oxoethyl)-3-oxazolidinecarboxylic acid 1,1-dimethylethyl ester (10.75 g) in dry dichloromethane (225 ml) at room temperature and is under nitrogen, was added 2-(trimethylsilyl)thiazole ( 10.6 ml). The mixture was then stirred at room temperature for 18 h. The reaction mixture was evaporated to dryness and the residues dissolved in THF (27 ml) and tetrabutylammonium fluoride ( 1.0M
in THF, 6 ml) added. The mixture was then stirred at room temperature for 2 h. The resultant mixture was evaporated to dryness, water (80 ml) added, and the mixture was extracted with 3o dichloromethane four times. The combined organic extracts were washed with brine, dried (MgS04) and concentrated to an oil. The crude mixture of diastereomers was purified by chromatography (silica, 20 to 60% ethyl acetate/isohexane as eluent) to give the (4S, 25~
isomer (7.6 g) as a pale yellow oil.
MS APCI +ve m/z 329 (M+H]+.
s ~ H NMR 400MHz (CDC13) 7.71 ( 1 H, d), 7.28 ( 1 H, d), 5.14 ( 1 H, m), 5.07 ( 1 H, m), 4.20 ( 1 H, m), 4.05 ( 1 H, m), 3.85 ( 1 H, m), 2.20-2.50 (2H, m), 1.48 ( 15H, m).
Further elution gave the (4S, 2R) isomer (6.4 g) as a colourless solid.
io MS APCI +ve m/z 329 [M+H]+.
H NMR 400MHz (CDC13) 7.72 ( 1 H, d), 7.28 ( 1 H, d), 5.68 ( 1 H, d); 4.94 ( 1 H, m), 4.35 ( 1 H, m), 4.04 '( 1 H, m), 3.71 ( 1 H, d), 2.42 ( 1 H, m), 1.90 ( 1 H, m), 1.62 (3 H, s), 1.53 (3 H, s), 1.51 (9H, s).
is b) 1,1-Dimethylethyl (4S)-4-f (2R)-2-(5-chloro-2-cyano-4-fluorophenoxy)-2-(2-thiazo~l)ethyll-2,2-dimeth~-3-oxazolidinecarbox To a solution of the ,(4S, 2R) isomer from step(a) (3 g) and 4-chloro-2,5-difluorobenzonitrile (1.59 g) in dry THF (100 ml) containing dry DMF (10 ml) at room temperature was added sodium hydride (60% in oil, 385 mg). After the addition was zo complete the mixture was stirred for 18 h and then poured into water (60 ml) and extracted with diethyl ether (3 times). The combined organic extracts were washed with brine and dried (MgS04). The mixture was evaporated to dryness to give an oil which was purified on silica gel eluting with 20 to 25% ethyl acetate in isohexane. The title compound was isolated as a yellow coloured oil (4.0 g, 91 %).
zs MS APCI +ve "'/z 482/4 [M+H]+.
c) 2-ff 1R 3S)-3-Amino-4-hydroxy-1-(2-thiazol l~but~lloxyl-4-chloro-5-fluorobenzonitrile ethanedioate 3o To a solution of the product from step (b) (4.0 g) in methanol ( 100 ml) was added a solution of 4M HCl in dioxane. The mixture was stirred at 20 °C for 1.5 h, then evaporated to dryness. The residue was dissolved in aqueous sodium bicarbonate solution and extracted with ethyl acetate (four times). The combined extracts were washed with brine, dried (MgS04) and purified by chromatography (silica, ethyl acetate, then 10%
(7M
ammonia in methanol) in dichloromethane as eluents) to give a mixture which was concentrated and dissolved in a mixture of ethanol and acetonitrile. A
solution of oxalic acid (730 mg) in diethyl ether was added and the resultant mixture was evaporated to dryness then recrystallised from a mixture of ethanol, acetonitrile and diethyl ether to give the title compound (2.14 g) as a white solid.
io MS APCI +ve m/z 342/4 [M+H]+.
H NMR 400MHz (d6-DMS O) 8.07 ( 1 H, d), 7.8 9 ( 1 H, d), 7.84 ( 1 H, d), 7.70 ( 1 H, d), 6.24 ( 1 H, m), 3.67 ( 1 H, m), 3 .5 5 ( 1 H, m), 3 .29 ( 1 H, m), 2.30-2.44 (2H, m).
Example 9 is 2-ff(1R,3S)-3-Amino-4-h day-1-(5-isothiazol~)butyllox~l-4-chloro-5-fluoro benzonitrile Hydrochloride a) 1,1-DimethMethyl (4S)-.4-f (2S)-2-hydroxy-2-(5-isothiazolyl)ethyll-2,2-dimethyl-3-zo oxazolidinecarboxylate and 1,1-DimethMethyl (~4f~-4-f(2R)-2-hydrox~2-(5-isothiazolyl)ethyll- 2,2-dimethyl-3-oxazolidinecarbox A solution of isothiazole (1.42 g) in dry THF (50 ml) under a nitrogen atmosphere was cooled to -78 °C and butyl lithium (1.6M in hexanes, 10.3 ml) added dropwise keeping the temperature below -70 °C. The resulting red solution was stirred at -78 °C for 1 h, then a zs solution of 1,1-dimethylethyl (4,5~-2,2-dimethyl-4-(2-oxoethyl)-3-oxazolidinecarboxylate (4 g) in dry THF (20 ml) was added over 5 minutes. After the addition was complete the cooling was removed and the mixture stirred for 30 minutes. The reaction mixture was poured into water (150 ml) and the products extracted into diethyl ether (2 x 150 ml). The combined extracts were dried (MgS04) and concentrated to an oil. Purification by 3o chromatography (silica, 50% isohexane in diethyl ether as eluent) gave the (4S, 2S) sub-title compound (600 mg) as a colourless oil.

MS APCI +ve m/z 329 [M+H]+.
Further elution gave the (4S, 2R) sub-title compound (500 mg) as a colourless oil.
s MS APCI +ve '"/z 329 [M+H]+.
b) 2-ff(1R,3S)-3-Amino-4-h day-1-(5-isothiazolyl)butylloxy]-4-chloro-5-fluoro benzonitrile Hydrochloride ~o A solution of the (4S, 2R) isomer from step (a) (500 mg) in a mixture of dry THF (20 ml) and dry DMF (2 ml) was treated with 4-chloro-2,5-difluorobenzonitrile (416 mg). To this mixture under nitrogen was added sodium hydride (60% dispersion in mineral oil, 91 mg).
The mixture was then stirred for 3h at 20 °C. The reaction mixture was poured into water (100 ml), and the products extracted into diethyl ether (2 x 100 ml). The combined extracts is were dried over (MgS04) and concentrated to an oil. The major product was isolated by column chromatography on silica gel (25% diethyl ether/ isohexane as eluent) and dissolved in methanol (5 ml). The solution was treated with 4M HCl in dioxane (2 ml) and stirred for 2 h. Concentration of the solution to dryness and trituation with acetonitrile afforded the title compound (190 mg) as a colourless solid.
2o MS APCI +ve m/z 342 [M+H]+.
'H NMR 400MHz (db-DMSO) 8.57 (lH,s), 8.07 (IH, d), 8.1 (3H, br s), 7.67 (1H, d), 7.54 ( 1 H, s), 6.5 ( 1 H, dd), 5.41 ( 1 H, t), 3.7-3.5 (2H, m), 3.25 ( 1 H, br m), 2.4-2.2 (2H, m).
is Example 10 4-ff(1R,3S)-3-Amino-4-hydroxv--1-1-phen l~bu llthio]-6-methoxy-3-pyridinecarbonitrile (E)-butenedioate 3o a) Phenylmethyl (3S)-3-ff( l,l-dimethylethoxy)carbonyllamino]-4-hydroxy-butanoate A solution of 4-(phenylmethyl) N [(1,1-dimethylethoxy)carbonyl]-1-(2,5-dioxo-1-pyrrolidinyl)) L-aspartate (75.0 g) in THF (200 ml) was added over 1 h to a suspension of sodium borohydride (6.84 g) in THF (60 ml),and water (90 ml) at -5 °C
(internal temperature kept below 15 °C). Further sodium borohydride (6.8 g in two batches) was s added and 'stirred for 45 min. The mixture was poured into cold, stirred, half saturated ammonium chloride solution (600 ml) and extracted with ethyl acetate (twice).
The organic layers were dried (MgS04) and evaporated to give the sub-title compound as a waxy solid (56.24 g).
~o MS APCI +ve m/z 210 [M+H-BOC].+.
~H NMR 300MHz (CDCl3) 7.41-7.27 (5H, m), 5.24-5.10 (3H, m), 4.15-3.96 (1H, m), 3.71 (2H, d), 2.69 (2H, d), 1.44 (9H, s).
b) Phen 1y methyl (4S1-3-f(1,1-dimethylethoxy)carbonyll-2,2-dimethyl-4-oxazolidine-~s acetate 2-Methoxypropene (46 ml) was added over 20 min to a solution of the product from step a) (74.88 g) 2,2-dimethoxypropane (30 ml) and p-toluenesulfonic acid (1.21 g) in dichloromethane (300 ml) at 0 °C and stirred at 0 °C for 1 h and at 20 °C for 1 h. 1M
NaHC03 was added and the mixture was extracted with dichloromethane (3 x 200 ml). The 20 organic layers were dried (MgSOa) and evaporated to give a colourless oil which was dissolved in toluene (300 ml), 2,2-dimethoxypropane (45 ml) and p-toluenesulfonic acid ( 1.2 g) added and the mixture was heated at 80 °C for 2 h. On cooling, K2C03 was added and the mixture was extracted with ethyl acetate (twice). The organic layers were dried (MgS04) and evaporated~to give the sub-title compound (83.8 g) as a pale yellow oil.
is ~H NMR 300MHz (CDC13) 7.36-7.28 (5H, m), 5.12 (2H, d), 4.38-3.97 (2H, m), 3.84 (1H, d), 3.05-2.48 (2H, m), 1.62-1.50 (6H, m), 1.46 (9H, s).
c) (4S~-3-f ( 1,1-Dimeth ley thox,v)carbonyll-2,2-dimethvl-4-oxazolidineacetic acid 3o A suspension of palladium on carbon ( 10%, 3.8 g) and the product from step b) (83.8 g) in ethanol (250 ml) was stirred under hydrogen (4 atmospheres pressure) for 3.5h (5.3 1 hydrogen uptake). The mixture was filtered through celite and evaporated.
Ethyl acetate (100m1) and 1M KZC03 (200 ml) were added and the organic layer was separated and further extracted with 1M K2C03 (40 ml) and 1M NaHC03 (40 ml). The aqueous layers were washed with ethyl acetate, combined and acidified at 0 °C by dropwise addition of 4M HCl (130m1). The aqueous was extracted with ethyl acetate (3 x 200 ml) and the s organic layers were dried (MgS04) and evaporated to give the sub-title compound as a pale orange gum (56.24 g), which slowly crystallised.
'H NMR 300MHz (CDCl3) 4.33-4.12 ( 1 H, m), 4.09-4.00 ( 1 H, m), 3.86 ( 1 H, d), 3.02-2.77 (1H, m), 2.62-2.50 (1H, m), 1.62-1.54 (6H, m), 1.53 (9H, s).
io dl 1,1-Dimethylethyl 4S1-4-f 2- methoxymethylamino)-2-oxoethyll-2,2-dimethyl-3-oxazolidinecarboxylate N, O,-Dimethylhydroxylamine hydrochloride (21.4 g), EDCI (41.94 g), N
methylmorpholine (24 ml) and DMAP (26.4 g) were added to a solution of the product is from step c) (59.2 g) in CHzCl2 (400 ml) at 0 °C and then stirred at 20 °C for 18 h. 2M
HCl (200 ml) was added, the organic layer was separated and the aqueous was further extracted twice. The organic layers were washed with 2M HCl (50 ml) and NaHC03 (2 x 100 ml), combined, dried (MgS04) and evaporated to give the sub-title compound (60.2 g).
2o MS APCI +ve m/z 303 [M+H]+.
1H NMR 300MHz (CDCl3) 4.38-4.19 (1H, m), 4.08 (1H, dd), 3.87 (1H, t), 3.70 (3H, s), 3.17 (3H, s), 3.07-2.45 (2H, m), 1.63-1.42 (15H, m).
e) 1,1-Dimethylethyl (4512,2-dimethyl-4-(2-oxo-2-phenylethyl)-3-oxazolidinecarboxylate is Phenyl magnesium bromide (231 ml, 1M in THF) was added over 15 min to a solution of the product from step d) (60.1 g) in THF (360 ml) at -10 to -5 °C and stirred for 2 h.
Further phenyl magnesium bromide (7 ml, 3M in ether) was added and stirred at 0 °C for 1 h then quenched by the addition of saturated NH4Cl (250 ml) and 2M HCl (150m1). The mixture was extracted with ethyl acetate (thrice) and the organic layers were washed with 3o brine, combined, dried (MgS04) and evaporated to give the sub-title compound (64.8 g) as an off white solid.

'H NMR 300MHz (CDC13) 7.98 (2H, d), 7.64-7.40 (3H, m), 4.50-4.35 (1H, m), 4.15-4.05 (1H, m), 3.88-3.65 (2H, m), 3.49-3.36 and 3.25-3.01 (1H, m), 1.70-1.35 (15H, m).
f) 1,1-Dimeth 1y ethyl (4S1 -4-f(2S)-2-hydroxy-2-phen 1y ethyll- 2,2-dimethYl s oxazolidinecarboxylate Borane (176 ml, 1M in THF) was added to a solution of (R) methyl-CBS-oxazaborolidine (16 ml, 1M in toluene) in THF (20 ml) and cooled to -20 °C. A solution of the product from step e) (64.6 g) in THF (200 ml) was added over 1.5 h, keeping the internal temperature below -15 °C, and then stirring at this temperature for 22 h. Methanol (40 ml) io was added slowly and the solution was evaporated and then azeotroped with methanol to give a pale yellow oil (69 g). Ether and 1M KHS04 (20 ml) were added and the mixture was filtered and evaporated. Purification by chromatography (silica, 40-60 petrol/ether as eluent) gave the sub-title compound (37.4 g) as a white solid, identical with the major product from Example 1 step a).
is Further elution gave the (4S, 2R) isomer as a white solid (20.0 g) identical with the minor product from Example 1 step a).
~l 1.1-Dimethvlethvl. (4514-f(2Rl-2-(benzovlthio)-2-phenvlethvll-2.2-dimethvl-20 oxazolidinecarboxylate Diisopropyl azodicarboxylate (21.5 ml) in THF (20 ml) was added dropwise to a solution of triphenylphosphine (28.73 g) in THF (230 ml) at -10 °C and the white suspension was stirred for 30 min. A solution of the product from step f) (17.58 g) and thiobenzoic acid (12.8 ml) in THF (100 rnl) was added over 45 min at -10 °C and then stirred at -10 °C to 4 Zs °C for 18 h. The solvent was removed in vacuo, ether added and stirred until a precipitate formed. The mixture was filtered and the solids washed with isohexane/ether ( 1:1 ). The solution was washed with aqueous NaHC03 and the aqueous layer extracted with ether.
The combined organic layers were dried (MgS04), evaporated and purified by chromatography (silica, 40-60 petrol/dichloromethane ( 1:1 then 0:1 ) as eluent) to give a 3o solid. This was crystallised from isohexane at -78 °C to give the sub-title compound (14.76 g) as a white solid, identical with the major product from Example 1 step b).

1H NMR 300MHz (CDC13) 7.93 (2H, d), 7.61-7.21 (8H, m), 4.79 (1H, dt), 4.18-3.83 (3H, m), 2.64-2.35 ( 1 H, m), 2.23-2.09 ( 1 H, m), 1.62-1.41 ( 15H, m).
h) 2-Chloro-5-(4 5-dihydro-4,4-dimethyl-2-oxazolyl)-pyridine s A suspension of 2-chloropyridine-4-carboxylic acid (100 g) in thionyl chloride (370 ml) was heated at 80°C for 4 h. The reaction mixture was evaporated in vacuo, the residue azeotroped with toluene and then taken up into dichloromethane (300 ml) The solution was added dropwise over 1 h at 0 °C to a solution of 2-amino-2-methylpropanol (118.8 g) in dichloromethane (300 ml) and then stirred at 20 °C for 16 h. Water (500 ml) was added io and the mixture was extracted with dichloromethane (5x500 ml). A solid suspension, which formed during extraction, is the required intermediate amide and needs extensive extraction. The organic layer was dried (MgS04) and evaporated to leave the intermediate amide (125.5 g).
This was suspended in dichloromethane (200 ml) at 0 °C and thionyl chloride (100 ml) was is added dropwise and stirred for 1 h. A thick precipitate formed and more dichloromethane (300 ml) is added and reaction stirred for a further hour. The solvent was removed in vacuo to give the product as the hydrochloride salt (120 g).
1H NMR 300MHz (CD30D) 9.03 ( 1 H, t), 8.42 ( 1 H, dd), 7.80( 1 H, dd), 4.96 (2H, s), 1.68 zo (6H, s).
The solid was suspended in water (800 ml) and treated with solid NaHC03 (ca.
70 g portion-wise) until gas evolution ceased. The mixture was extracted with dichloromethane (2 x 500 ml), dried (MgS04) and evaporated to give the sub-title compound (99.5 g).
Zs 'H NMR (CDC13) 8.90 (1H, dd), 8.17 (1H, dd), 7.37 (1H, dd), 4.14 (2H, s), 1.39 (6H, s).
i) 5-(4 5-Dihydro-4,4-dimethyl-2-oxazolyl)-2-methoxy-pyridine The product from step h) (99.5 g) in methanol (500 ml) vas treated with sodium methoxide 30 (0.61 mol of a 25wt% solution in methanol) and heated at reflux for 12 hrs.
The solvent was removed under reduced pressure and the residue taken up in water (200 ml) and extracted with dichloromethane (2 x 300 ml). The extract was dried (MgS04) evaporated to dryness to give the sub-title compound as an orange oil (85 g).
1H NMR 300MHz (CDCl3) 8.68 ( 1 H, dd), 8.10 ( 1 H, dd), 6.75 ( 1 H, dd), 4.09 (2H, s), 3.98 (3H, s), 1.37 (6H, s).
j,~ 5-(4,5-Dihydro-4,4-dimethyl-2-oxazolyl)-2-methoxy-4-(methylthio)-p ' To 2,2,6,6-tetramethylpiperidine (51.22 g) in THF, under nitrogen, at 0°C, was added n-BuLi (227 ml of 1.6M solution in hexanes) dropwise and stirred for 15 min. The reaction io mixture was cooled to -78°C and the product from step i) (43.97 g) in THF (50 ml) was added dropwise. The cooling bath was removed and the reaction temperature was allowed to warm up to -20 °C and kept at this temperature for 30 min. It was then cooled to -78°C
and dimethyldisulphide (80 ml) was dripped in. The reaction mixture temperature rose to -30°C during this addition. The cooling bath was then removed and the reaction was stirred ~s to room temperature for 12 h. The resulting red solution was quenched with water and concentrated to ca. 600 ml on a rotary evaporator. Water was added (500 ml) and the mixture was extracted with ethyl acetate (2 x 600 ml). The combined organics were washed with citric acid (500m1 of 1M aqueous solution), dried (MgS04) and evaporated to give the sub-title compound as a pale yellow solid, (58.5 g).
zo 'H NMR 300MHz (CDCl3) 8.50 (1H, s), 6.52 (1H, s), 4.04 (2H; s), 3.97 (3H, s), 2.40 (3H, s), 1.40 (6H, s).
k) 6-Methoxy-4-(methylthio)-3-pyridinecarbonitrile is A stirred solution of the oxazoline from step j) (45 g) in pyridine (350m1) was treated with phosphorus oxychloride (68 ml) and the mixture stirred under reflux for 4.5 h.
The dark brown solution was cooled to room temperature and cautiously poured onto ice ( 1 kg). The resulting suspension was filtered and the solid washed with water (300 ml), 2M
HCl ( 100 ml) and again with water (300m1). The damp product was dissolved in dichloromethane 30 (600m1) and the solution dried (MgS04). Activated charcoal was added (15g) and the suspension filtered. Concentration of the filtrate and trituration of the solid with 40-60 petrol gave the sub-title compound as a very pale pink solid (26 g).

'H NMR 300MHz (CDC13) 8.31 (1H, s), 6.51 (1H, s), 3.98 (3H, s), 2.52 (3H, s).
1) 6-Methoxy-4-(meth~sulfonyl)-3-pyridinecarbonitrile s A solution of the product from step k) (13 g) in dichloromethane (150 ml) was cooled to 0 °C and treated with portion-wise addition of MCPBA (21.74g of ~57%
purity) over 10 min. The mixture was allowed to slowly warm up to 20 °C. After 8 hrs LC/MS indicated a mixture of sulphoxide / sulphone products (72:28). Additional MCPBA was added (7.2 g) and after a further 4 hrs LC/MS indicated a 50:50 mixture of products. More MCPBA was io added (12 g) and stirnng continued for a further 2 h before reaction was complete. The reaction was cooled to 0 °C and treated with excess aqueous sodium metabisulphite solution. The organic layer was washed with sat. NaHC03 (3 x 200 ml), dried (MgS04) and evaporated to give the sub-title compound as a white solid ( 11.2 g).
is 1H NMR300MHz (CDCl3) 8.69 (1H, s), 7.47 (lH,s), 4.09 (3H, s), 3.28 (3H, s).
m) 1,1-Dimeth l~ethyl~4f)-41~2R)-2-f (5-cyano-2-methoxy-4-pyridinyl)thiol-2-phenylethyll 2,2-dimethyl-3-oxazolidinecarboxylate A solution of the product from step g) (lO.Og) in methanol (75 ml) at 20 °C was treated 2o with 7 M ammonia in methanol (SO.mI) every hour for eight hours. The methanol was evaporated and the residue was dissolved in dry DMF (100 ml). The product from step 1) (4.8 g) was added and allowed to dissolve, followed by caesium carbonate (7.38 g) and the mixture was stirred at 20 °C for 18 h. Ethyl acetate (200 ml) and water (200 ml) were added,and the aqueous layer was separated and washed with ethyl acetate (2x 100 ml). The is combined ethyl acetate layers were washed with water (3x 200 ml) and brine, dried (MgS04), filtered and concentrated in vacuo to leave a crude yellow gum.
Purification by chromatography (silica, 30% ethyl acetate in isohexane as eluent) gave the sub-title compound as a translucent foam (7.4 g).
3o MS APCI +ve m/z 470 ([M(+H)]+).

' H 300MHz (CDC13) 8.51 ( 1 H, s), 7.56 (2H, d), 7.37 (2H, t), 7.27 ( 1 H, t), 6.87-6.83 ( 1 H, m), 4.98-4.84 (1H, m), 4.14-3.60 (3H, m), 3.85 (3H;-s), 2.30-1.85 (2H, m), 1.49-1.38 ( 1 SH, s).
s n) 4-[j(1R 3,5~-3-Amino-4-hydroxy-1-phenylbutyllthiol-6-methoxy-3-pyridinecarbonitrile (~-butenedioate To a solution of the product from step m) (7.1 g) in methanol (100 ml) at 0 °C, was added 4MHC1 in dioxane (100 ml). The mixture was stirred at 20 °C for 2 h and the solvent was removed in vacuo. The residue was partitioned between aqueous sodium bicarbonate (200 io ml) and dichloromethane (200 ml). The aqueous phase was extracted with dichloromethane (2x 100 ml) and the combined extracts were dried (MgS04), filtered and concentrated in vacuo to give the title compound free base as a pale yellow oil (4.8 g).
MS (APCI+ve) m/z 330 [M(+H)~+.
is 'H 300MHz (CDC13) 8.27 (1H, s), 7.43 (2H, d), 7.34 (2H, t), 7.27 (1H, t), 6.65 (lI-I, s), 4.75 (1H, dd), 3.90 (3H, s), 3.51-3.27 (2H, m), 2.71-2.63 (1H, m), 2.12-1.88 (2H, m).
A solution of this compound in methanol (SO ml) was added to a solution of fumaric acid (1.6 g) in methanol (50 ml) and stirred at 20 °C. The solvent was removed in vacuo and the zo residue was triturated with acetonitrile. The precipitate was collected and washed with acetonitrile, and dried to give the title compound as a white solid (S.1 g), m.p. 172-173 °C.
MS (APCI+ve) m/z 330 [M(+H)]+.
'H SOOMHz (DMSO-d~) 8.53 (1H, s), 7.55 (2H, d), 7.39 (2H, t), 7.30 (1H, t), 7.00 (1H, s), zs 6.45 (2H, s), 5.15 ( 1 H, dd), 3.89 (3H, s), 3.38 (2H, ddd), 2.73-2.65 ( 1 H, m), 2.25-2.01 (2H, m) Example 11 4-ff(1R,3R)-3-Amino-4-h dery-1-phenylbutyl]thiol-6-methoxy-3-pyridinecarbonitrile ~E)-butenedioate.
a) 1,1-Dimethylethyl (4R~-4-(2-oxo-2-phenylethyl)-2,2-dimethyl-3-oxazolidinecarboxylate s The sub-title compound was prepared from 4-(phenylmethyl) N [(1,1-dimethylethoxy)carbonyl]-D-aspartate, the enantiomer of the starting material in Example step a), by the methods of Example 10 steps a) to e).
MS APCI +ve'"/z 320 [M+H]+.
io 1H NMR 300MHz (d6-DMSO) 7.98 (2H, d), 7.61-6.83 (3H, m), 4.69 (1H, bs), 4.10 (1H, t), 3.83-3.68 (2H ,bm), 3.15 (1H, m), 1.66-1.42 (15H, m) b) 1 1-Dimeth l~yl (4R)-4-f(2R)-2-(benzoylthio)-2-phenylethyll-2,2-dimeth oxazolidinecarbox~ate is The sub-title compound was prepared by the methods of Example 10 steps f) and g) from the product from step a). The chiral reduction (step f) was carned out using (R) methyl-CBS-oxazaborolidine.
MS APCI +ve m/z 342 [M+H]+.
Zo 1H NMR 400MHz (d6-DMSO) 7.86 (2H, d), 7.85-7.24 (8H, m), 4.77 (1H, m), 4.01-3.87 (2H, m), 3.62 (lH,bs), 2.16 (2H, m), 1.47-1.36 (15H, m) c 4-ff 1R,3R)-3-Amino-4-hydroxy-1-phenylbutyllthiol-6-methoxy-3-pyridinecarbonitrile, (E~-butenedioate.
is The title product was prepared by the methods of Example 10 steps m) to n).
M.p. 221-223 °C.
MS APCI +ve m/z 330 (M+H]+.
IH NMR 400MHz (d6-DMSO) (90°C) 8.54 (1H, s), 7.54 (2H, d), 7.39 (2H, t), 7.30 (1H, so t), 6.87 (1H, m), 6.45 (2H, m), 5.09 (1H, m), 3.88 (3H, s), 3.61-3.55 (2H, m), 2.88 (1H, m), 2.33-2.09 (2H, m) Example 12 4-f f (1 S 3R)-3-Amino-4-hydroxy-1=phen l~tyllthio]=6-methoxy-3-pyridinecarbonitrile, s (~-butenedioate a) 1 1-Dimeth~yl (4R)-4-f (2S)-2-(benzo l~)-2-phenylethyll-2,2-dimethyl-3-oxazolidinecarboxylate.
The sub-title compound was prepared by using (S~ methyl-CBS-oxazaborolidine catalyst in ~o the chiral reduction of the product from Example 11 step a) following the procedure of Example 10 steps f) to g).
MS APCI +ve m/z 342 [M+H]+.
'H NMR 400MHz (d6-DMSO) 7.85 (2H, d), 7.63 (1H, t), 7.50 (2H, t), 7.42 (2H, d), 7.34 is (2H, t), 7.27 ( 1 H, t), 4.80 ( 1 H, m), 3.95 ( 1 H, m), 3.85-3.13 (2H,m), 2.14 (2H, m), 1.45-1.36 ( 15H, m) b~[f ( 1 S,3R)-3-Amino-4-h~droxy-1-phenylbutyllthiol-6-methoxy-3-pyridinecarbonitrile,(E)-butenedioate 2o The title compound was prepared by the methods of Example 10 steps m) to n) from the product of step a). M.p. 162.5-163 °C.
MS APCI +ve m/z 330 [M+H]+.
'H NMR 400MHz (d6-DMSO) 8.53 (1H, s), 7.55 (2H, d), 7.38 (2H, t), 7.30 (1H, t), 7.00 is ( 1 H, s), 6.44 ( 1 H, s), 5.12 ( 1 H, m), 3.89 (3H, s), 3.36-3.26 (2H, m), 2.62 ( 1 H, m), 2.22-2.08 (1H, m), 2.01-1.95 (1H, m) Example 13 4-ff(1S 3S)-3-Amino-4-hydroxy-1-phen~butyllthio]-6-methoxy-3-p~ridinecarbonitrile (E)-butenedioate a) 4-f(2S)-2-(Benzoylthio)-2-phenylethyll-2,2-dimethyl-1,1-dimethyleth l s oxazolidinecarboxylate The sub-title compound was prepared from the minor isomer of Example 1 step a), following the method of Example 10 step g).
MS APCI +ve m/z 342 [M+H]+.
~o 'H NMR 300MHz (db-DMSO) 7.91 (2H, d), 7.57-7.23 (8H, m), 4.76 (1H, m), 4.17-3.61 (3H, m), 2.50-2.18 (2H,m), 1.66-1.41 (15H, m), b) 4-[[(1S,3S)-3-Amino-4-hydroxy-1-phenylbutyl]thiol-6-methoxy-3-p;rridinecarbonitrile,(E)-butenedioate is The title compound was prepared by the methods of Example 10 steps m) to n) from the product of step a). M.p. 213-228°C.
MS APCI +ve ~'/z 330 [M+H]+.
~H NMR 400MHz .(d6-DMSO) 8.53 (1H, s), 7.53 (2H, d), 7.39 (2H, t), 7.30 (1H;
t), 7.96 zo ( 1 H, s), 6.43 (2H, s), 5.08 ( 1 H, t), 3.88 (3 H, s), 3.58 (2H, m), 2.86 ( 1 H, bs), 2.25-2.28 ( 1 H, m), 2.08 ( 1 H, m).
Example 14 zs 4-ff(1R 3S)-3-Amino-4-hydrox~l-phenylbut~lthiol-6-(difluoromethoxy)-3-pyridinecarbonitrile (E)-butenedioate a) 5-(4 5-Dihydro-4,4-dimethyl-2-oxazolyl)-3-(methylthio)-2-pyridinnol To 2,2,6,6-tetramethylpiperidine (5.7 g) in THF, under nitrogen, at 0 °C, was added n-BuLi 30 (16.4 ml of 2.5M solution in hexanes) dropwise and stirred for 15 min. The reaction mixture was cooled to -78 °C and S-(4,S-dihydro-4,4-dimethyl-2-oxazolyl) 2-pyridinol (2.6 g) in THF (75 ml) was added dropwise. The cooling bath was removed and the reaction temperature was allowed to warm to -20 °C and kept at this temperature for 2 h. It was then cooled to -78 °C and dimethyldisulphide (4.9 ml) was added dropwise. There was an exotherm to -30 °C during this addition. The cooling bath was then removed and the s reaction was stirred at 20 °C for 12 h. Water (50m1) was added and the resulting mixture was extracted with dichloromethane (2 x 60 ml). The combined organics were washed with citric acid (SOmI of 1M aqueous solution), dried (NazS04) and evaporated to give. the sub-title compound as a pale yellow solid, (3.75 g) which was a 50:50 mixture of starting reagent and product by NMR.
io MS APCI +ve m/z 239 (M+H]+.
1H NMR 300MHz (d6-DMSO): (product); 7.92 (1H, s), 6.28 (1H, s), 4.06 (3H, s), 2.50 (2H, s), 1.35 (6H, s) is b) 2-(Difluoromethoxy)-5-(4,5-dihydro-4,4-dimethyl-2-oxazolyl)-4-(methylthio)-pyridine The product from step a) (2.6 g) in NMP (5 ml) was treated with sodium hydride (1.7 g of a 60% dispersion in mineral oil) and heated at SO °C for 3 h.
Chlorodifluoromethane was then bubbled through the reaction mixture for 1 h. Water (SO ml) was added and the resulting mixture was extracted with ethyl acetate (3 x 60 ml). The combined organics zo were washed with aqueous NaHC03, then brine, dried (MgS04) and evaporated to obtain an oil. The residue was purified by chromatography (silica, isohexane/ethyl acetate.as eluent) to give sub-title compound (0.6 g) as an oil.
MS APCI +ve m/z 289 [M+H]+.
is ' H NMR 400MHz (d6-DMSO) 8.50 ( 1 H, s), 7.50 ( 1 H, t), 6.68 ( 1 H, s), 4.06 (2H, s), 2.43 (3H, s), 1.56 (6H, s) c) 6-(Difluoromethoxy)-4-(methylthio)-3-pyridinecarbonitrile The sub-title compound was prepared by the method of Example 10 step k) using the 3o product from step b).
~H NMR 300MHz (d6-DMSO) 8.30 (1H, s), 7.49 (1H, t), 6.68 (1H, s), 2.57 (3H, s) d) 6-(Difluoromethoxy~methylsulfonyl)-3-pyridinecarbonitrile The product from step c) (0.36 g) in acetone (15 ml) was treated with NaHC03 (1.l g), then a solution of oxone (3 g) in water ( 1 S ml) was added dropwise and stirred at room s temperature for 5. h. Water was added and the resulting mixture was extracted with ethyl acetate (3 x 50 ml). The combined organics were washed with water, brine and dried (MgS04) and then evaporated to give the sub-title compound as a pale yellow solid, (0.25 g) io 'H NMR 300MHz (d6-DMSO) 8.75 (1H, s), 7.67 (1H; s), 7.51 (1H, t), 3.38 (3H, s) ej4-j[(1R 3S1-3-Amino-4-hydroxy-l:phen l~tyllthiol-6-(difluoromethoxy)-3-Ryridinecarbonitrile (E~-butenedioate The title compound was prepared by the method of Example 10 steps m) to n) using is product from step d). M.p. 144-146 °C.
MS APCI +ve '"/z 366 [M+H]+.
1H NMR 400MHz (db-DMSO) 8.61 (fH, s), 7.65 (1H, t), 7.65-7.37 (7H, m), 6.54 (2H, s), 5.34 ( 1 H, m), 3.47 (2H, m), 2.88 ( 1 H, bs), 2.27 (2H, m).
Example 1 S
2-[f(1R 3R)-3-Amino-4-hydroxv-1-phenylbutyllthiol-6-meth ~~l-3-pyridinecarbonitrile Hydrochloride 2s a) 1 1-Dimethylethyl (4R) 4-[,(2R)-2-[(3-Cyano-6-methyl-2-pyridinyl)thiol-2-phenylethyll-2 2-dimethyl-3-oxazolidinecarboxylate The product from Example 11 step b), ( 190 mg) and' 2-chloro-6-methyl-3-pyridinecarbonitrile (220 mg) were dissolved in 7M ammonia in methanol (5 ml) and 3o stirred at ambient temperature for 18 hr. The reaction mixture was evaporated to dryness and the residue was purified by chromatography (silica, dichloromethane as eluent) to give sub-title compound (110 mg) as a gum.
MS APCI +ve m/z 4S4 [M+H]+.
b) 2iff(1R 3R)-3-Amino-4-hydroxy-1-phenylbutyllthiol-6-methyl-3-pyridinecarbonitrile Hydrochloride A solution of the product from step a) ( 110 mg) in 4M HCl in dioxane (2 ml) was stirred at 20 °C for 2 hr. The solvent was removed in vacuo and the residue triturated with io acetonitrile to give the title compound as a white solid (42 mg).
MS APCI +ve m/z 314 [M+H]+.
~H NMR 300MHz (d6-DMSO) 8.1 (1H, d), 7.54-7.28 ($H, m), 5.36 (1H, t), 5.22-5.17 ( 1 H, m) 3 .81-3.75 ( 1 H, m), 3.62-3.54 ( 1 H, m) 3 .32 (3H, s), 2.8-2.7 ( I
H, m), 2.5 3-2.46 ( 1 H, is m).
Example 16 41j(1R 3S~-3-Amino-4-hydroxy-1-phenylbutyllthiol-6-(2H3)methoxy-3-Zo pyridinecarbonitrile (E7-2-butenedioate a) S-(4,S-Dihydro-4,4-dimethyl-2-oxazolyl)-2-(ZH3 methoxy=pyridine Sodium hydride (800 mg) was added to a solution of the product from Example ~10 step h) (2.1 g) and methyl-d3-alcohol-d (720 mg) in DMF (SO ml). The reaction mixture was is heated at 6S °C for 2 h and then allowed to cool to room temperature. The mixture was poured into water (1000 ml) and extracted with ethyl acetate (twice). The combined organics were dried (MgS04), filtered and concentrated in vacuo to give the sub-title compound (2.3 g) as a colourless oil.

1 H NMR 400MHz (CDC13) 8.68 ( 1 H, s), 8.10 ( 1 H, d), 6.72 ( 1 H, d), 4.09 (2H, s), 1.3 7 (6H, s).
b) 5-(4,5-Dihydro-4,4-dimethyl-2-oxazol~)-2-(2H3)methoxy-4-(methylthio)-pyridine s The sub-title compound was prepared by the method of Example 10 step j) using the product from step a).
MS APCI +ve m/z 256 ([M(+H))+) io c 6- 2H3 Methoxy-4-(meth lay-3-pyridinecarbonitrile The sub-title compound was prepared by the method of Example 10 step k) using the product from step b).
MS APCI +ve m/z 184 ([M(+H)]+).
d) 6-(2H3 Methox~!-4-(methylsulfonyl)- 3-pyridinecarbonitrile A solution. of Oxone (11.1 g) in water (40 ml) was added to a suspension of the product from step c) ( I .l g) in acetone (40 ml) and sodium bicarbonate (4.16 g). The reaction mixture was then stirred at room temperature for 24 h. Water and ethyl acetate were then 2o added until a complete solution was achieved. The organic phase was separated and dried (MgS04), filtered and concentrated to give the sub-title compound (1.3 g) as a colourless solid.
MS APCI +ve '"/z 216 ([M(+H)]+) e) I ,1-Dimethylethyl (4,51-4-[(2R)-2-f 2-(2H3 methoxy -S-methyl-4-p.~yl)thiol-phen~lethy~-2,2-dimethyl-3-oxazolidinecarboxylate The sub-title compound was prepared by the method of Example 10 step m) using the product from step d).
MS APCI +ve m/z 373 ([M(+H)-BOC)~.

fl 4-ff(1R,3,5~-3-Amino-4-hydroxy-1=phenylbutyllthiol-6-(2H3)methoxy-3-pyridinecarbonitrile (~-2-butenedioate The title compound was prepared by the method of Example 10 step n) using the product s from step e). M.p. 181-182 °C.
'H NMR 400MHz (db-DMSO) 8.53 (1H, s), 7.54 (2H, d), 7.38 (1H, t), 7.30 (1H, t), 7.00 ( 1 H, s), 6.45 ( 1 H, s), 5.12 ( 1 H, m), 3.33 (3H, m), 2.64 ( 1 H, m), 1.99 ( 1 H, m), 1.85 ( 1 H, m).
io Example 17 2-[[(1R,3,S'~-3-Amino-4-hydroxy-1 phen 1y butyllthio]-6-ethyl-3-pyridinecarbonitrile ethanedioate us a) 2-Chloro-6-ethyl-3 pyridinecarbonitrile To a stirred solution of 2-chloro-6-methyl-3-pyridinecarbonitrile (1.52 g) in dry DMF (10 ml) under a nitrogen atmosphere, was added iodomethane (2.5 ml). Sodium hydride (60%
dispersion, 400 mg) was then added to the stirred solution. After the initial exothermic 2o reaction subsided the mixture was stirred for 0.5 h then diluted with water (50 ml), and the products extracted with diethyl ether (100 ml). The dried extract ( MgS04) was concentrated to dryness, and the residue was purified by chromatography (silica, isohexane/diethyl ether 4:1 ) to give the sub-title compound (700 mg).
2s 'H 400MHz (CDC13) 7.8 (1H, d), 7.16 (1H, d), 2.81 (2H, q), 1.26 (3H, t).
b) 1,1-Dimethylethyl (4514-f(2R)-2-fL-cyano-6-ethyl-2-pyridinyl)thiol-2-phenylethyll-2,2-dimethyl-3-oxazolidinecarboxylate A solution of the product from step a) (200 mg) and product from Example 1 step b) (442 3o mg) were stirred at ambient temperature in 7M ammonia in methanol (15 ml) for 2 h. The mixture was then concentrated to dryness and the residue purified by chromatography ~. (silica isohexane/diethyl ether 7:3) to afford the sub-title compound (260 mg).
MS APCI +ve '"/z 468 ([M+H]~
s c) 2-[[(1R,3S~-3-Amino-4-h dy roxy-1-phen l~butyl]thiol-6-ethyl-3-pyridinecarbonitrile ethanedioate The title compound was prepared from the product from step b), according to the procedure described in Example 8 step c), and was isolated as a colourless solid 80 mg.
io 'H 400MHz (DMSO-d6) 8.09 (1H, d), 7.5 (2H, d), 7.37-7.19 (4H, m), 5.35 (1H, t), 3.58-3.44 (2H, m), 3.09-3.04 (2H, m), 2.85 (2H, q), 2.35-2.25 (2H, m), 1.26 (3H, t).
MS APCI +ve ~'/z 328 ([M+H]+).
~s Example 18 2- [[( 1 R, 3,5~-3 -Amino-4-hYdroxy-1-phenvlbutyl l thiol-6-( 1-methyl ether pyridinecarbonitrile ethanedioate a) 2-[j(1R)-2-j(4f~-2,2-Dimethyl-4-oxazolidinyll-1-phenylethyllthiol-6-(1-methyleth zo 3 pyridinecarbonitrile The sub-title compound was synthesised from 2-chloro-6-(1-methylethyl)-3-pyridinecarbonitrile according to the procedure described in Example 17 step b).
MS APCI +ve m/z 382 ([M+H]+).
z5 b) 2-ffl'1R,3,S~-3-Amino-4-hydroxy-1 phenylbuty~thio~-6-(1-methylethyl)-3-pyridinecarbonitrile ethanedioate .
The title compound was synthesised from the product from step a) according to the procedure described in Example 8 step c).
MS APCI +ve '"/z 342 ([M+H]+) H 300MHz (DMSO-d6) 8.1 ( 1 H, d), 7.5-7.19 (6H, m), 5.37 ( 1 H, t), 3.6-3.4 (2H, m), 3.16-3.0 (2H, m), 2.28 (2H, t), 1.27 (3H, d), 1.23 (3H, d).
Example 19 s 2-[[(1R 3S~-3-Amino-4-hydroxy-1-phen 1y butyllthiol-6-methyl-3-pyridinemethanol ethanedioate a) Methyl 6-methyl-2-(methylsulfonyl)pyridine-3-carboxylate ~o A mixture of methyl 2-chloro-6-methylpyridine-3-carboxylate (1 g) and sodium methanesulphinate (1.6 g) in dry DMSO (10 ml) was heated at 120°C for 4 h. The cooled reaction mixture was diluted with water ( 100 ml) and the products extracted into ethyl acetate (2x100 ml). The dried extracts (MgS04) were concentrated to dryness and the residue purified by chromatography (silica, diethyl ether). The sub-title compound was is isolated as a pale pink oil (600 mg).
MS APCI +ve m/z 230 ([M+H]+).
b~ Methyl 2-[(( 1 R)-2-[(4,5~-3-f ( 1,1-dimethylethoxy)carbonyll-2,2-dimethyl-zo oxazolidinyll-1-phenyleth~lthiol-6-methyl pyridine-3-carboxylate The sub-title compound was prepared from the product from step a according to the procedure described in Example 10 step m).
MS APCI +ve '"/z 487 ([M+H]+):, c1 1.1-Dimethvlethvl (4S1-4-f (2R)-2-f f 3-(hvdroxvmethvl)-6-methyl-2-pyridinyllthiol-2-~henvleth~]-2,2-dimethyl-3-oxazolidinecarboxylate A solution of the product from step b) (500 mg) in dry THF at ambient temperature, and under a nitrogen atmosphere was treated with lithiun borohydride (2M solution in THF 5x5 3o ml aliquots over 3 days). After 5 days the mixture was diluted with water (100 ml) and the excess reagent destroyed by addition of citric acid. The mixture was then extracted with ethyl acetate (2x75 ml) and the combined extracts dried (MgS04) and concentrated. The crude product was purified by chromatography (silica diethyl ether/ isohexane 7:3) to afford the title compound as a colourless gum (400 mg).
s MS APCI +ve m/z 459 ([M+H]+) d) 2-(f(1R,3S1-3-Amino-4-hydroxy-1-Qhenylbut~]thiol-6-methyl-3-pyridinemethanol ethanedioate The title compound was prepared from the product from step c) according to the procedure ~o described in Example 8 step c).
~H 300MHz (DMSO-d~/D20) 7.6-7.2 (6H, m), 6.97 (1H, d), 5.28 (1H, t), 4.36 (2H, s), 3.63-3.38 (2H, m), 3.15 (1H, t), 2.5 (3H, s), 2.31 (2H, t).
MS APCI +ve '"/z 319 ([M+H]+).
is Example 20 6-Acetyl-2-ff(1R,3S)-3-amino-4-hydroxy-1-phenylbutyl~thio]-3-pyridine carbonitrile Hydrochloride a) 6-Acetyl-2-(methylsulfonyl)-3-pyridine carbonitrile 6-Acetyl-2-(methylthio)-3-pyridine carbonitrile (170mg) was dissolved in acetone (40 ml) and water (8m1). Oxone ( 1.66 g) was added and the suspension stirred at room temperature for 68 h. 0.5M aqueous sodium thiosulphate solution (50 ml) was added and the solution 2s stirred for 0.5h. The reaction was then extracted with ethyl acetate (3 x 50 ml) and combined organic extracts washed with water (3x20 ml), dried (MgS04) and evaporated in vacuo. The residue was purified by chromatography (silica, hexane/ethyl acetate as eluent) to give the sub-title compound ( 109mg) as a white solid.
~H NMR 300MHz (CDC13) 8.40 (2H, dd), 3.47 (3H, s), 2.78 (3H, s).

b) (4S)-1,1-Dimethylethyl 4-~(2R)-2-L(6-ace~yano-2-pvridinyl)thiol-2-phen let~hy_ll-2,2-dimethyl-3-oxazolidinecarboxylate The sub-title compound was prepared by the method of Example 10 step m) using the product of step a) (100 mg) and the product of Example 10 step g) (199 mg).
The product s was purified by chromatography (silica, hexane/ethyl acetate as eluent) to give the sub-title compound ( 125 mg) as a colourless oil.
'H NMR 400MHz (CDCl3) 7.89 (1H, s), 7.71 (1H, d), 7.46 (2H, t), 7.32 (2H ,t), 7.23 (1H
,d), 5.16 ( 1 H, m), 4.16 ( 1 H, m), 3.86 ( 1 H, m), 3.51 ( 1 H, m), 2.75-2.62 (3H, d), 2.60-2.33 ~o (1H, m), 2.23-2.10 (1H, m), 1.59-1.40 (15H, m).
c) 6-Acetyl-2-f~(1R,3S)-3-amino-4-hydroxy-1 phenylbutyl]thiol-3-pyridine carbonitrile Hydrochloride The product of step b) ( 125 mg) was dissolved in methanol (20 ml) and the solution treated is with 4M HCl in dioxane (10 ml). The reaction was stirred at room temperature for 3 h. The solvent was removed in vacuo and the residue triturated with 20% ethyl acetate in hexane.
The solid was filtered and dried to give the title compound (75 mg) as a pale yellow solid.
M.p. 78 °C.
2o MS APCI +ve m/z 342 ([M+H]+).
'H NMR 300MHz (DMSO-D6) 8.41 (1H, dd), 8.16 (3H, s), 7.76 (1H, dd), 7.58 (2H, d), 7.39 (2H, t), 7.30 (1H, m), 5.46 (1H, t), 5.35 (1H, t), 3.59-3.40 (2H, m), 3.07 (1H, s), 2.76 (3H, d), 2.34 (2H, t).
Zs Example 21 2-f f ( 1 R,3 S)-3-Amino-4-hydroxy-1-phenylbuty~thiol-6-(hydroxymethyl)-3-pyridine carbonitrile (E)-butenedioate 3o a) 6-(Hydroxymethyl)-2-(methylthio)-3-pyridine carbonitrile 6-Formyl-2-(methylthio)nicotinonitrile (500 mg) was dissolved in ethanol (50 ml) and the solution treated with sodium borohydride ( 117 mg). The reaction was stirred at room temperature for 1 h and then quenched with water (50 ml). The reaction was concentrated in vacuo down to approximately 50 ml and then extracted with ethyl acetate (3x60 ml).
Combined organic extracts were washed with water (2 x 40 ml), dried (MgS04) and evaporated in vacuo to give the sub-title compound (478 mg) as a white solid.
~H NMR 300MHz (CDC13) 7.79 ( 1 H, d), 7.07 ( 1 H, d), 4.80 (2H, d), 3.18 ( 1 H, t), 2.65 (3H, s).
~o b~ 6-[ff(1,1-DimethMethyl)dimethylsilylloxylmeth~]'-2-(methylthio)-3-pyridine carbonitrile The product from step a) (473 mg) was dissolved in dichloromethane (80 ml) and treated with imidazole ( 196 mg). The solution was cooled to 0 °C and t-BDMSCI
(434 mg) added.
~ s The reaction was stirred at room temperature for 18 h and then quenched with water (50 ml). Extracted with ethyl acetate (3x60m1) and combined organic extracts washed with (2 x 40 ml), dried (MgS04) and evaporated in vacuo. to give the sub-title compound (731 mg) as a white solid.
2o 'H NMR 300 MHz (CDC13) 7.79 (1H, d), 7.27 (1H, d), 4.80 (2H, s), 2.59 (3H, s), 0.98 (9H, s), 0.13 (6H, s).
c) 6-off(1,1-DimethvlethMldimethylsilylloxy]methyll-2-(methylsulfonyl)-3-pyridine carbonitrile is The product from step b) (725 mg) was dissolved in acetone (80 ml), water (40 ml) and aqueous saturated sodium bicarbonate solution (20 ml). The suspension was treated with oxone (4.1 g) and the reaction stirred at room temperature for 24 h. The reaction mixture was concentrated in yacuo to approximately 70m1 and extracted with ethyl acetate (3 x 60 ml). Combined organic extracts were washed with water (3 x 40 ml), dried (MgS04) and 3o evaporated in vacuo to give the sub-title compound (715 mg) as a white solid.

~H NMR 300MHz (CDC13) 8.24 (1H, d), 7.91 (1H, d), 4.92 (2H, s), 3.35 (3H, s), 0.97 (9H, s), 0.16 (6H, s).
d) 1,1-Dimethylethyl (4S)-4-[~2R)-2-[j3-cyano-6-[f[(1,1-dimeth~yl)dimethYlsilyll s oxylmethyll-2-pyridinyl]thiol-2-phenylethyll-2,2-dimethyl-3-oxazolidinecarboxylate The sub-title compound was prepared by the method of Example 10 step m) using the product of step c) (222 mg) and the product of Example 10 step g) (300 mg).
The product was purified by chromatography (silica, hexane/ethyl acetate as eluent) to give the sub-title compound ( 180 mg) as a colourless oil.
io 'H NMR 300MHz (CDC13) 7.75 (1H, d), 7.39 (2H, d), 7.33-7.18 (4H, m), 5.20-5.00 (1H, m), 4.89-4.67 (2H, m), 4.17-4.04 ( 1 H, m), 3.85 ( 1 H, s), 3.72-3.42 ( 1 H, m), 2.66-2.33 ( 1 H, m), 2.17 (1H, dd), 1.57-1.39 (15H, m), 0.96 (9H, d), 0.14 (6H, d).
~s e) 2-f[(1R,3S)-3-Amino-4-h droxy-1-phenylbutyl]thiol-6- hvdroxymethyl)-3-p '~ndine carbonitrile (E)-butenedioate The title compound was prepared, by the method of Example 10 step n) using the product of step d) (175mg), as an off white solid (100mg). M.p. 147-149 °C.
zo 1H NMR 300MHz (db-DMSO) 8.17 (1H, d), 7.50 (2H, d), 7.39-7.23 (4H, m), 6.46 (2H, s), 5.33 (1H, t), 4.69 (2H, dd), 3.51-3.34 (2H, m), 2.83 (1H, t), 2.35-2.14 (2H, m).
MS APCI +ve "'/z 330 ([M+H]+) zs Example 22 2-ff(1R, 3S1-3-Amino-4-hydroxy-1-phenylbutyl]thiol-3wridinecarbonitrile (E)-butenedioate 3o a) 1,1-Dimethylethyl (4S~- 4-[(2R)-2-f (3-cyano-2-pyridinyl)thiol-2 phen 1Y
ether]-2,2-dimethyl-3-oxazolidinecarbox~late The product from Example 10 step g) (318 mg) was dissolved in 7M ammonia in methanol (40 ml) and 2-chloro-3-cyanopyridine (100 mg) added. The reaction was stirred at room temperature for 24 h. The solvent was removed in vacuo and the residue purified by chromatography (silica, ethyl acetate/hexane as eluent) to give the sub-title compound (200 s mg) as a colourless oil.
MS APCI +ve '"/z 440 ([M+H]+).
b) 2-ff(1R 3S)-3-Amino-4-hydroxy-1-phen l~yllthiol-3-pyridinecarbonitrile (~-io butenedioate The title compound was prepared, by the method of Example 10 step n) using the product of step a) as an off white solid (125 mg). M.p. 67-69 °C.
' H NMR 300MHz d6-(DMSO) 8.74 ( 1 H, d), 8.21 ( 1 H, dd), 7.50 (2H, d), 7.32 (4H, m), Is 6.46 (2H, s), 5.37 (1H, t), 3.53-3.33 (2H, m), 2.90-2.80 (1H, m), 2.36-2.17 (2H, m).
MS APCI +ve m/z 300 ([M+H]+).
Example 23 zo (_Q'S 8'R)- (3-Amino-b-[(2,5-dichloro-4-p~yl)thiobenzenebutanoll Hydrochloride a~2,5-Dichloro-4-(methylthio)-Qyridine To DMF (3.13 ml) in THF (20 ml), under nitrogen, at 0 °C, was added nBuLi (8.9 ml of a 2.5M solution in hexanes) dropwise and stirred for 15 min. The reaction mixture was zs . added dropwise to a solution of 2,5-dichloropyridine (3 g) in THF (20 ml) at -78 °C. After 2 h, dimethyldisulfide (2.4 ml) was added and the reaction temperature was allowed to warm up to 0 °C. Water was added and the mixture was extracted with ethyl acetate. The combined organics were dried (NazS04) and evaporated to give the sub-title compound as a yellow solid, (3 g).
'H NMR 400MHz (CDC13) 8.18 ( 1 H, s), 7.02 ( 1 H, s), 2.50 (3H, s).

b) 2,5-Dichloro-4-(methylsulfonyl)-p 'dine The sub-title compound was prepared by the method of Example 5 step b) using the product from Example 23 step a). White solid.
s 'H NMR 300MHz (CDC13)'8.39 (1H, s), 7.91 (1H, s), 2.90 (3H, s).
c~(~ 'S SCR)- ~i-Amino-8-f(2,5-dichloro-4-pyridin~)thiobenzenebutanoll-Hydrochloride The title compound was prepared by the method of Example 10 steps m & n) using the ~o products from Example 23 step b) and Example 10 step g). Final purification was by reversed phase HPLC followed by treatment with HCI.
MS (APCI+ve) '"/z 343 [M(+H)]+.
1H 400MHz (DMSO-d6) 8.37 (1H, s), 8.08 (3H, bs), 7.58 (3H, m), 7.41 (2H, t), 7.33 (1H, ~s tt), 3.54-3.50 (2H, m), 3.41 (1H, dd), 2.96 (1H, bs), 2.33-2.14 (2H, m).
Example 24 2-f f ( 1R 3S)-3-Amino-4-h d~ rox~l -phen 1v butyllthio]-5-fluoro-6-methoxy-3-zo pyridinecarbonitrile-(~-butenedioate al 2-Chloro-5-fluoro-6-methoxy-3-pyridinecarbonitrile A solution of 2,6-dichloro-5-fluoro-3-pyridinecarbonitrile (2.33 g) and sodium methoxide (1.9 ml of a 25 wt. % solution in methanol) in DMF was heated at 50°C
for 16 h. Further zs sodium methoxide (0.57 ml) was added and the heating continued for a further 48 h. Water was added and the mixture was extracted with diethyl ether. The combined organics were washed with water, dried (NazS04) and evaporated to give the sub-title compound as a white solid (2.08 g).
30 ~H NMR 300MHz (CDCl3) 7.58 (1H, d), 4.11 (3H, s).

b) 2-ff(lR,3f)-3-Amino-4-hydroxy-1-phenylbutyllthiol-5-fluoro-6-methoxy-3-pyridinecarbonitrile-(~-butenedioate The title compound was prepared by the method of Example 10 steps m & n) using the products from Example 24 step a) and Example 10 step g).
s MS (APCI+ve) m/z 348 (M(+H)]+, ~ H 400MHz (DMSO-d6) 8.20 ( 1 H, d), 7.49 (2H, d), 7.36 (2H, t), 7.28 ( 1 H, m), 5.28 ( 1 H, dd), 4.13 (3H, s), 3.31 (2H, m), 2.67 ( 1 H, m), 2.21 ( 1 H, m), 2.08 ( 1 H, m).
io Exam 1p a 25 4-ff(1R,351-3-Amino-4-hydroxy-1-phenylbut llthio]-6~dimethylamino)-3-pyridinecarbonitrile (E~-2-butenedioate is a) 5-(4,5-Dihydro-4,4-dimethyl-2-oxazolyl)-N,N dimethyl-2-pyridinamine A mixture of the product from Example 10 step h) .(2.1 g), 2.0 M
dimethylamine/THF (80 ml) and toluene (80 ml) was heated at 120 °C in a sealed tube for 16 h.
The mixture was then evaporated to dryness and the residue purified by chromatography (silica, ethyl acetate as eluent) to give the sub-title compound ( 1.55 g) as a pale orange solid.
1 H NMR 400MHz (CDC13) 8.64 ( 1 H, s), 7.97 ( 1 H, d), 6.48 ( 1 H, d), 4.05 (2H, s), 3.14 (6H, s), 1.36 (6H, s).
b) 5-(4,5-Dihydro-4,4-dimethyl-2-oxazol~l)-N,N dimethyl-4-(methylthio)-2-pyridinamine zs The sub-title compound was prepared by the method of Example 10 step j) using the product from step a) and purified by chromatography (silica, isohexane/ethyl acetate as eluent).
MS APCI +ve m/z 266 ((M(+H)]+) c) 6-(Dimethylamino~methylthio)-3-pyridinecarbonitrile The sub-title compound was prepared by the method of Example 10 step k) using the product from step b).
MS APCI +ve m/z 194 ([M(+H)]+) d7 6-(Dimeth~lamino)-4-(methylsulfon l~)-3-pyridinecarbonitrile, The sub-title compound was prepared by the method of Example 16 step d) using the product from step c).
io MS APCI +ve m/z 226 ([M(+H)]+).
e) 1,1-Dimethylethyl (4,S'~-4-[~2R)-2-f f 5-cyano-2-(dimethylamino)-4-pyridinyllthiol2-phenyleth~l-2,2-dimethyl-3-oxazolidincarboxylate The sub-title compound was prepared by the method of Example 10 step m) using the is product from step d).
MS APCI +ve m/z 483 ([M(+H)]+).
fl 4-f f ( 1 R,3f~-3-Amino-4-h dery-1-phenylbut~]thiol-6-(~dimethylamino)-3- .
zo pyridinecarbonitrile (~-2-butenedioate The title compound was prepared by the method of Example 10 step n) using the product from step e). M.p. 175-177 °C
'H NMR 400MHz (d6-DMSO) 8.29 (1H, s), 7.55 (2H, d), 7.38 (2H, t), 7.29 (1H, t), 6.47 zs (4H, d), 5.11 ( 1 H, m), 3.3 8 (2H, m), 3.05 (6H, s), 2.75 ( 1 H, m), 2.17 ( 1 H, m), 2.04 ( 1 H, m) Example 26 30 4-ff(lR,3f~-3-Amino-4-hey-1-Qhenylbutyl]thio~-6-(methylamino)-3-pyridinecarbonitrile dihydrochloride a) 5-(4,5-Dihydro-4,4-dimet~l-2-oxazolyl)-N methyl-2-pyridinamine A mixture of the product from Example 10. step h) (2.1 g), 2.0 M
methylamine/THF (30 ml) and toluene (30 ml) was heated at 120 °C in a sealed tube for 16 h.
The mixture was then evaporated to dryness and the residue purified by chromatography (silica, ethyl acetate as eluent) to give the sub-title compound (700 mg) as a beige solid.
1 H NMR 400MHz (CDCl3) 8.60 ( 1 H, s), 7.97 ( 1 H, d), 6.36 ( 1 H, d), 4.85 ( 1 H, br s), 4.06 (2H, s), 2.96 (3H, d), 1.36 (6H, s).
~o b) 1 1-Dimethyleth~l f5~4,5-dihydro-4,4-dimethyl-2-oxazolyl)-2-pyridinyllmethyl carbamate Di-tert-butyl dicarbonate (1.47 g) was added to a solution of the product from step.a) (700 mg) in dichloromethane ( 10 ml). 4-(Dimethylamino)pyridine (42 mg) was then added and the mixture was stirred at room temperature for 16 h. The reaction mixture was poured is onto water and the organic phase separated, dried (MgS04), filtered and evaporated to dryness to give the sub-title compound (900 mg) as colourless oil.
MS APCI +ve '"/z 306 ([M(+H)]+).
zo c) l,l-Dimethyleth~[5-(4,5-dihydro-4,4-dimethyl-2-oxazolyl)-4-(meth l Qyridinyllmethyl- carbamate The sub-title compound was prepared by the method of Example 10 step j) using the product from step b).
zs MS APCI +ve "'/z 252 ([M(+H)]+).
d) 1 1-Dimethylethyl f5-cyano-4-(methylthio)-2-pyridinyllmethyl carbamate The sub-title compound was prepared by the method of Example 10 step k) using the product from step c).
MS APCI +ve m/z 180 ([M(+H)]+).

e) 1,1-Dimethylethyl- r5-cyano-4-(methylsulfonyl)-2-pyridinyllmethyl carbamate The sub-title compound was prepared by the method of Example 16 step d) using the product from step d).
s MS APCI +ve m/z 212 ([M(+H)]+) fl 1,1-Dimethylethyl 4S) 4-f f f 5 ~ano~ f ( 1,1 dimethylethoxy)carbonyllmethylaminol-4-pyridinyllthiol-2-phenylethYl12,2-dimethyl- 3-oxazolidinecarboxylate The sub-title compound was prepared by the method of Example 10 step m) using the io product from step e).
MS APCI +ve m/z 569 ([M(+H)]+).
~) 4-ff(1R,3S~3-Amino-4-hvdroxy-1-phenylbutyllthiol-6-(methylamino)- 3-is pyridinecarbonitrile dihydrochloride To a solution of the product from step f) (490 mg) in methanol (20 ml), was added 4M HCl in dioxan (20 ml). The mixture was stirred at room temperature for 8 h and the solvent was removed in vacuo. The residue was triturated with diethyl ether and the title compound (340 mg) was collected by filtration as a white solid. M.p. 206-208 °C.
MS APCI +ve m/z 329 ([M(+H)]+).
1H NMR 400MHz (d6-DMSO) 8.21 (1H, s), 8.18 (2H, br s), 7.53 (2H, m), 7.36 (2H, m), 7.28 ( 1 H, m), 6.66 ( 1 H, s), 5.04 ( 1 H, t), 3.45 (2H, m), 2.99 ( 1 H, br s), 2.83 (3 H, s), 2.31 (2H, t).
2s Example 27 ~J~~S,B'R)- ~3-Amino-8-[(5-bromo-2-methox~pyridinyl)thiol-benzenebutanol (~-2-butenedioate 3o a) 5-Bromo-2-methoxy-4-(methylthio)-pyridine To N,N diisopropylamine ( 11.7 ml) in THF (45 ml), under nitrogen, at 0 °C, was added nBuLi (32.5 ml of a 2.5M solution in hexanes) dropwise and stirred for 15 min.
The reaction mixture was cooled to -78 °C and a solution of 5-bromo-2-methoxypyridine ( 14.3 g) in THF (10 ml) was added dropwise. After 2 h, dimethyldisulfide (13.8 ml) was added s followed by THF (20 ml). The reaction temperature was allowed to warm up to -40 °C.
The reaction was poured into aqueous ammonium chloride solution, and the mixture extracted with ether. The combined organics were dried (Na2S04) and evaporated.
Trituration with cold isohexane gave the sub-title compound as a beige solid, (11 g).
io 'H NMR 300MHz (CDC13) 8.08 (1H, s), 6.45 (1H, s), 3.91 (3H, s), 2.44 (3H, s).
b) 5-Bromo-2-methoxy-4-(methylsulfonyl)pyridine The sub-title compound was prepared by the method of Example 16 step d) using the is product from step a).
MS APCI +ve "'/z 267/269 ([M(+H)]+) c) 1,1-Dimethylethyl (4S)-4-[(2R)-2-[(5-bromo-2-methoxY 4-pyridinyl)thiol-2-zo phenyleth;rll-2,2-dimethyl-3-oxazolidinecarboxylate The sub-title compound was prepared by the method of Example 10 step m) using the product from step b).
MS APCI +ve "'/z 523/525 ([M(+H)]+).
2s d~~3~S 8'R)- ~a-Amino-b-[(5-broino-2-methoxy-4-pyridin 1)~ thiol-benzenebutanol (~-2-butenedioate, The title compound was prepared by the method of Example 10 step n) using the product from step c). M.p. 178-180 °C
MS APCI +ve °'/z 383/385 ([M(+H)]+) 1H NMR 400MHz (d6-DMSO) 8.17 (1H, s), 7.56 (2H, d), 7.38 (2H, t), 7.29 (1H, t), 6.86 ( 1 H, s), 6.47 (2H, s), 4.98 ( 1 H, m), 3.79 (3H, s), 3.30-3.41 (2H, m), 2.72 ( 1 H, m), 2.17 ( 1 H, m), 2.04 ( 1 H, m).
Example 28 ~~3~5 S1R) Q-Amino-8-L(5-chloro-2-methoxy-4-pyridinyl)thiol-benz~nebutanol (E)-butenedioate ao a15-Chloro-2-methoxy-4-(methylthio)-pyridine The product from Example 23 step a) (1.4 g) in methanol (20 ml) was treated with sodium methoxide (8.2 ml of a 25wt% solution in methanol) and heated at reflux for 48 hrs. The solvent was removed under reduced pressure and the residue was partitioned between water (50 ml) and dichloromethane (50 ml). The organic phase was dried (MgS04) and is evaporated to dryness. Purification by chromatography (silica, dichloromethane as eluent) gave the sub-title compound (345 mg) as a white solid.
MS APCI +ve m/z 189 ([M(+H)]+) zo b) 5-Chloro-2-methoxy-4-(meth~sulfonyl)p riy dine The sub-title compound was prepared by the method of Example 5 step b) using the product from step a).
MS APCI +ve m/z 222/224 ([M(+H)]+) c) 1 1-DimethMethyl 1,452 4-f 2R)-2-f(5-chloro-2-methoxy-4-pyridinyl)thiol-2-phenylethvll-2,2-dimethyl-3-oxazolidinecarboxylate The sub-title compound was prepared by the method of Example 10 step m) using the product from step b).
MS APCI +ve 'T'/z 479/481 ([M(+H)]+) d~((3'S,8'R)- ~i-Amino-8-f(S-chloro-2-methoxy-4-p rr~yl)thiol- benzenebutanol (E)-2-butenedioate The title compound was prepared by the method of Example 10 step n) using the product s from step c). M.p. 191-193 °C.
MS APCI +ve m/z 339-341 ([M(+H)]+) 'H NMR 400MHz (db-DMSO) 8.08 (1H, s), 7.56 (2H, d), 7.38 (2H, t), 7.29 (1H, t), 6.88 ( 1 H, s), 6.48 (2H, s), 4.99 ( 1 H, m), 3.80 (3H, s), 3.30-3.41 (2H, m), 2.73 ( 1 H, m), 2.18 ~o (1H, m), 2.05 (1H, m).
Example 29 4-~f ( 1 R,3 S)-3-Amino-4-h d~~phenylbutyllthiol-6-ethox~pyridinecarbonitrile, (E)-is butenedioate a) 5-(4,5-Dihydro-4,4-dimethyl-2-oxazolyl)-2-ethoxy-pyridine The product from Example 10 step h) (2'.1 g) in DMF (50 ml) was treated with ethanol (1.2 ml) and sodium hydride (0.8 g of a 60% dispersion in mineral oil) and heated at 60 °C for 20 20 h. Water (200 ml) was added and the resulting mixture was extracted with ethyl acetate (2 x 150 ml). The combined organics were dried (MgS04) and evaporated to give the sub-title compound as a yellow oil, (3.0 g).
MS APCI +ve °'/z 221 [M+H]+.
Zs ' H NMR 400MHz (d6-DMSO) 8.66 ( 1 H , s), 8.09 ( 1 H, d), 6.71 ( 1 H, d), 4.40 (2H, q), 4.09 (2H, s), 1.26-1.41 (9H, m).
b 6-Ethoxy-4-(methylthio)-3-pyridinecarbonitrile The sub-title compound was prepared by the method of Example 10 steps j) to k) from the 3o product from step a).

MS APCI +ve m/z 195 [M+H]+.
1H NMR 400MHz (d6-DMSO) 8.28 (1H, s), 6.49 (1H, s), 4.42 (2H, q), 2.52 (3H, s), 1.38 (3H, t).
s c) 6-Ethoxy-4-(methylsulfonyl)-3-pyridinecarbonitrile The sub-title compound was prepared by the method from Example 14 step d) from the product from step b).
1H NMR 400MHz (d6-DMSO) 8.67 (1H, s), 7.44 (1H, s), 4.52 (2H, q), 3.27 (3H, s), 1.42 io (3H, t) d) 4-ff(1R,3S'Z 3-Amino-4-hydroxy-1-phen 1y butyllthiol-6-ethoxy-3-pyridinecarbonitrile ~~-butenedioate The title compound was prepared by the method of Example 10 steps m) to n) using the is product from step.c). M.p. 169.5-171.5 °C.
MS APCI +ve "'/z 344 [M+H]+.
1H NMR 400MHz (db-DMSO) 8.52 (1H, s), 7.55 (2H, d), 7.39 (2H, t),,7.30 (1H, t), 6.98-( 1 H, s), 6.47 (2H, s), 5.13 ( 1 H, m), 4.34 (2H, q) 3 .40 (2H, m), 2.70 ( 1 H, m), 2.21 ( 1 H, m), zo 2.02 (1H, m), 1.30 (3H, t).
Example 30 3-ff(1R,3,S~-3-Amino-4-h dy roxy-1-phenylbuty~thio]-5-(trifluorometh~)-2-zs pyridinecarbonitrile Ethanedioate a) 1 1-Dimeth~yl, (4S1-4-[(2R)-2-ff2-cyano-5-(trifluoromethyl)-3-pyridinyllthiol-2-phenylethyl]-2,2-dimethyl-3-oxazolidinecarboxylate The sub-title compound was prepared by the method of Example 1 step c), using the 3o product from Example 1 step b) and 3-chloro-2-cyano-5-trifluoromethylpyridine.

MS APCI +ve m/z 408 [M+H-Boc]+.
b) 3-ff(1R 3,S'~-3-Amino-4-h dery-1-phenylbutyllthiol-5-(trifluoromethyl)-2-pyridinecarbonitrile ethanedioate s The title compound was prepared by the method of Example 1 step d), using the product of step a) to give the title compound as a white solid (133 mg). M.p. 147-149 °C.
MS APCI +ve m/z 368 [M+H]+.
~H NMR 400MHz (d6-DMSO) 8.98 (1H, s), 8.33 (1H, s), 7.34 (5H, m), 5.04 (1H, t), 3.58 i o ( 1 H, dd), 3.48 ( 1 H, 'm), 3 .OS ( 1 H, m), 2.3 3 ( 1 H, m), 2.18 ( 1 H, m).
Example 31 3-[[ 1R,3S~3-Amino-4-h~droxy-1-phenylbut 11~]-1,6-dihydro-5-methyl-6-oxo-2-~s pyridinecarbonitrile a) 3-Bromo-5-methyl-2-Q ridinecarbonitrile A solution of 3-bromo-2-fluoro-5-methylpyridine (J. Het. Chem. 1967, 641, 642) in dry DMSO (100 ml) was treated with sodium cyanide (1.48 g) and heated to 80 °C for 24 h.
zo The mixture was poured into brine, extracted with ethyl acetate and the organic layer dried (MgS04). The solvent was evaporated and the residue was purified by chromatography (silica, diethyl ether) to give the sub-title product as a pale yellow solid (3.0 g).
1H NMR 400MHz (CDCl3) 8.47 (1H, s), 7.84 (1H, s), 2.44 (3H, s).
2s b) 3-Bromo-5-meth~pyridinecarbonitrile-N-oxide A solution of the product from step a) (2.0 g) in glacial acetic acid (100 ml) was treated with 30% hydrogen peroxide (20 ml) and heated to 80 °C for 22 h. The mixture was evaporated, the residue triturated with hexane and the resulting solid collected to give the 3o sub-title product as a pale yellow solid (2.0 g).

MS APCI +ve '~/z 214 (M+H]+, 1H NMR 400MHz (CDCl3) 8.07 (1H, s), 7.35 (1H, s), 2.37 (3H, s).
c) 1 1-Dimethyleth 1y (4S~-4-f (2R)-2-f (2-cyano-5-meth~pyridinyl)thiol-2-phenylethyll-s 2 2-dimethyl-3-oxazolidinecarboxylate N-oxide The sub-title compound was prepared by the method of Example 1 step c), using the thiobenzoate of Example 1 step b) and the pyridine-N-oxide from step b) (0.43 g) to give a gum (1.25 g), which was used directly in step d).
io MS APCI +ve m/z 470 [M+H]+.
d) 1,1-Dimethylethyl (4,S'~-4-f(2R)-2-[f6- acetyloxy)-2-cyano-5-methyl-3-pyridinyllthiol-2-phen 1y ethyll-2,2-dimethyl-3-oxazolidinecarbox 1Y ate, A solution of the product from step d) in acetic anhydride (20 ml) was heated under reflux is for 4 h. The mixture was evaporated, the residue was dissolved in ethyl acetate and washed with water, then aqueous NaHC03 and dried (MgS04). The solvent was evaporated and the residue was purified by chromatography (silica, 20% ethyl acetate/hexane) to give the sub-title product as a viscous oil (0.45 g).
zo MS APCI +ve m/z 456 [M+2H-tBu]+.
e) 3-ff(1R 3,5~-3-Amino-4-hydroxy-1-phenylbutyllthio]-1,6-dihydro-5-methyl-6-oxo-2-QYridinecarbonitrile The title compound was prepared by the method of Example l, step d), using the product is of step d) to give the title compound as a white solid (131 mg), isolated as its free base.
MS APCI +ve "'/z 330 [M+H]+.
'H NMR 400MHz (d6-DMSO) 7.27 (1H, s), 7.26 (5H, m), 4.53 (1H, m), 3.23 (4H, m), 2.50 (1H, m), 2.12 (1H, m), 1.82 (1H, m), 1.97 (3H, s).
Example 32 3-[[( 1 R,3f~-3-Amino-4-hydrox~phenylbutyllthiol-5-chloro-2-pyridinecarbonitrile ethanedioate The title compound was prepared by the method of Example 10 steps m & n) using 3,5-dichloro-2-pyridinecarbonitrile and the product from Example 10 step g). After treatment with HCl the title compound was purified by reversed phase HPLC (to remove an , unwanted regioisomer) and then treated with ethanedioic acid to afford a white solid.
io MS (APCI+ve) m/z 334 ~M(+H)]+.
1H 400MHz (DMSO-d6) 8.66 (1H, d), 8.22 (1H, d), 8.03 (ca. 2H, vbs), 7.41-7.27 (5H, m), 4.97 ( 1 H, t), 3.55 ( 1 H, dd), 3.44 ( 1 H, dd), 3 .02 ( 1 H, m), 2.32 ( 1 H, m), 2.16 ( 1 H, dt).
Example 33 is 6-Amino-4-[[(1R,3S1-3-amino-4-h~roxy-1-phen l~butyllthiol-3-pyridinecarbonitrile (~-butenedioate a) 1,6-Dihydro-4-(methylsulfonyl)-6-oxo-3-pyridinecarbonitrile zo 6-Methoxy-4-(methylsulfonyl)-3-pyridinecarbonitrile from Example 10 step 1) (5.1 g) was dissolved in acetonitrile (200 ml) and sodium iodide (7.28 g) and trimethylsilylchloride (5.28 g) were added. The reaction was heated under reflux for 48 h and then cooled and the solvent evaporated in vacuo. The residue was partitioned between water ( 120 ml) and ethyl acetate ( 120 ml). After shaking, the layers were filtered and the solid collected and dried in zs a vacuum oven at 60 °C to give the sub-title compound as an off white solid (3.6 g).
1H NMR 400MHz (d6-DMSO) 13.15 (1H, bs), 8.58 (1H, s), 6.89 (1H, s), 3.39 (3H, s).
b) S-Cyano-4-(methylsulfonyl)-2-pyridinyl trifluoromethanesulfonate 3o Triflic anhydride. (0.1 ml) was added to a solution of the product from step a) (57 mg) and triethylamine (0.1 ml) in acetonitrile (2 ml) at -20 °C and stirred at -20 °C to 20 °C for 2 h. Water was added and the mixture was extracted with dichloromethane. The organic extracts were dried_(MgS04), evaporated and purified by chromatography (silica, dichloromethane as eluent) to give the sub-title compound (66 mg).
s ~H 300MHz (CDC13) 8.94 (1H, s), 7.91 (1H, s), 3.37 (3H, s).
c) 6-Amino-4-(methylsulfonvl)-3-pyridinecarbonitrile 0.5M Ammonia in dioxane (2 ml) was added to a solution of the product from step b) (164 mg) in THF (2 ml) and stirred for 16 h. The solvent was removed in vacuo and the residue io purified by chromatography (silica, isohexane/ethyl acetate as eluent) to give the sub-title compound (33 mg) as a white solid.
~H NMR (d6-DMSO) 8.57 (1H, s), 7.78 (2H, s), 7.05 (1H, s), 3.35 (3H, s).
is d) 1 1-Dimethylethyl (4,5~-4-f(2R)-2-f(2-amino-5-cyano-4-pyridinyl)thiol-2-phenyleth~1l-2,2-dimethyl-3-oxazolidinecarbox A solution of the product from Example 10 step g) (105 mg) in 7 Mammonia in methanol (5 ml) was stirred for eight hours. The methanol was evaporated and the residue was dissolved in dry acetonitrile (3 ml). The product from step c) (45 mg) and caesium zo carbonate (151 mg) were added and the mixture was stirred at 20 °C
for 1 h. Ammonium chloride solutiom was added and the mixture was extracted with ethyl acetate.
The organic extracts were dried (MgS04), evaporated and purified by chromatography (silica, isohexane/acetone as eluent) gave the sub-title compound (55 mg) as a white solid.
2s MS (APCI+ve) m/z 455 ~M(+H)]+.
IH 300MHz (CDCl3) 8.16 (1H, s), 7.38-7.30 (5H, m), 6.83 (1H, s), 5.22 (2H, s), 4.45 (1H, d), 3.97 (1H, t), 3.55 (1H, t), 2.93 (1H, d), 2.59 (1H, d), 2.29 (1H, q), 1.61-1.42 (15H, m).
e) 6-Amino-4-[[(1R,3S~-3-amino-4-hydroxyl-phenylbutyllthiol-3-pyridinecarbonitrile 30 (E1-butenedioate The title compound was prepared from the product of step d) by the method of Example 10 step n).

MS (APCI+ve) '~/z 315 [M(+H)]+.
~H NMR 400MHz (DMSO) 8.16 (1H, s), 7.51 (2H, d), 7.38 (2H, t), 7.31 (1H, t), 7.14 (2H, s), 6.62 ( 1 H, s), 6.50 (2H, s), 4.95 ( 1 H, s), 3.41-3.33 (2H, m), 2.78-2.70 ( 1 H, m), 2.29-2.19 s ( 1 H, m), 2.16-2.07 ( 1 H, m).
Example 34 3-[[( 1 R,3S1-3-Amino-4-hydroxy-1-phenylbutyl]thiol-5-methyl-2-pyridinecarbonitrile ~o a) 1,1-Dimeth~rlethyl (4f~-4-f (2R)-2-f (2-cyano-5-methyl-3-pyridinyl)thiol-2-phenylethyll-2,2-dimethyl-3-oxazolidinecarbox The sub-title compound was prepared by the method of Example 1 step c), using the thiobenzoate of Example 1 step b) and the bromopyridine from Example 31 step a) (0.17 g) is to give the product as a glass (0.19 g).
MS APCI +ve '"/z 398 [M+2H-tBu]+.
b) 3-[[(1R,3S~-3-Amino-4-hydrox~phen 1y butyllthiol-S-methyl-2-pyridinecarbonitrile zo The title compound was prepared by the method of Example 1 step d), using the product of step a) to give the title compound as a white solid (139 mg), isolated as its free base.
MS APCI +ve '"/z 314 [M+H]+.
'H NMR 400MHz (d6-DMSO) 8.41 (1H, s), 8.18 (2H, bs), 8.04 (1H, s), 7.43 (2H, d), 7.31 zs (3H, m), 5.32 ( 1 H, bt), 5.13 ( 1 H, m), 3.46 (2H, m), 2.93 ( 1 H, m), 2:35 (3H, s), 2.28 ( 1 H, m), 2.16 ( 1 H, m).
Example 35 4-f f ( 1R 3Sy-3-Amino-1-(2-fluorophenyl)-4-hydroxybutyllthiol-6-methoxy-3-pyridinecarbonitrile Ethanedioate a) 1 1-Dimethylethyl4-f(2S')-2-(2-Fluorophenyl)-2-hydroxyethyll-2,2-dimethyl-(4S~-3-s oxazolidinecarboxylate, and 1,1-Dimethyleth~2R)-2- 2-Fluorophen 1~2-hydroxyethyll-2,2-dimeth~l-(4S1-3-oxazolidinecarboxylate A stirred suspension of magnesium (243 mg) in THF (30 ml) under nitrogen was treated with 1,2-dibromoethane (2.44g) and warmed gently. An exotherm set in and the mixture began to reflux. After the metal had dissolved, the mixture was stored at room temperature io under nitrogen. A stirred solution of 3-bromofluorobenzene (1.17g) in THF
(10 ml) under nitrogen was treated at -65 to -70 °C with n-butyllithium (2.5 M in hexane, 2.26 ml, 5.67 mmol) and stirred at -70 °C for 30 min. The solution was treated at -65 to -70 °C with the solution of magnesium dibromide from above, stirred at -70 °C for 5 min, then. at 0 °C for 20 min. A stirred solution of 1,1-dimethylethyl 2,2-dimethyl-4-[(4S)-2-oxoethyl)-3-~s oxazolidinecarboxylate (1.21 g) in THF (20 ml) under nitrogen was treated at 0 °C with the Grignard reagent formed above, stirred at 0 °C for 30 min, then at room temperature overnight. The solution was quenched with saturated aqueous ammonium chloride and extracted with ether. The washed and dried (MgS04) extracts were evaporated and the residue was purified by chromatography (silica, ether/isohexane as eluent) to give the sub-2o title compound 1,1-dimethylethyl 4-[(2S~-2-(2-Fluorophenyl)-2-hydroxyethyl]-2,2-dimethyl-(4S~-3-oxazolidinecarboxylate as a white solid (600 mg).
'H NMR 300MHz (d4-MeOH) 7.38 (1H, s), 7.28 (4H, s), 7.12 (5H, d), 4.80-4.75 (9H, m), 4.00-3.79 ( 18H, m), 2.12-1.96 ( 11 H, m), 1.54-1.41 (96H, m).
zs Further elution gave the second sub-title compound 1,1-Dimethylethyl 4-[(2R)-2-(2-Fluorophenyl)-2-hydroxyethyl]-2,2-dimethyl-(4S)-3-oxazolidinecarboxylate as a white solid (429 mg).

'H NMR 300MHz (d4-MeOH) 7.40-7.37 (1H, m), 7.28 (1H, s), 7.12 (1H, d), 4.83-4.79 ( 1 H, m), 4.06 ( 1 H, s), 3.90-3.84 ( 1 H, m), 3.75-3.72 ( 1 H, m), 2.20 ( 1 H, s), 1.96-1.86 ( 1 H, m), 1.54-1.47 (15H, m).
s b 4-Mercapto-6-methoxy-3-pyridinecarbonitrile, A mixture of the product from Example 10, step I (1.0 g) and sodium hydrogen sulphide (790 mg) in ethanol (50 ml) was stirred for 2h and evaporated. The residue was taken up in water, treated with dilute hydrochloric acid until pH 6, and extracted with ethyl acetate.
The dried (MgS04) extracts were evaporated to give the sub-title compound as a tan ~o powder (741 mg).
'H NMR 300MHz (CDC13) 8.36 (1H, s), 6.72 (1H, s), 3.97 (3H, s).
c) 4-ff3~3S)-Amino-1(1R)-(2-fluorophenYl)-4-hydroxybutyllthiol-6-methoxy-3-is pyridinecarbonitrile Ethanedioate A stirred solution of triphenylphosphine (309 mg) and THF (10 ml) under nitrogen was treated at -5 to 0 °C with DIAD (238 mg), stirred at -5 °C for 20 min, and then cooled to -20 °C and stored. A mixture of the product from step b) (196 mg), and the product from step a) (589 mg) were stirred, treated with the above DIAD/ triphenylphosphine solution, Zo stirred overnight and evaporated. The residue was purified by chromatography (silica, ether/isohexane), taken up in methanol ( 10 ml), treated with 2M HCl in dioxan ( 10 ml), stirred for 2h and evaporated. The residue were purified by preparative reversed phase HPLC on a 19 x 50 mm Xterra C8 5 micron column using 10 to 60% acetonitrile in 2%
aqueous 0.880 ammonia solution over 6 min at 20 ml/min. UV detection by DAD.
The free is base was taken up in ether/ ethanol mixture, treated with a solution of oxalic acid in ethanol and evaporated. The residue was triturated with ether and residue was dried to give the title compound as a cream powder (31 mg), M.p. 179-185 °C.
MS APCI +ve m/z 348 [M+H]+.
30 'H NMR 300MHz (d4-MeOH) 8.58 (1H, s), 7.62 (1H, t), 7.43-7.37 (1H, m), 7.31-7.23 (2H, m), 6.98 ( 1 H, s), 5.22 ( 1 H, t), 3.91 (3H, s), 3.56-3.40 (4H, m), 3.05-3.02 ( 1 H, m), 2.40-2.17 (2H, m).

Example 36 2-~f ( 1 R,3S)-3-Amino-1-(4-fluorophenyl)-4-hydroxybutylloxyl-6-trifluoromethyl-3-s Qyridinecarbonitrile Ethanedioate a) 1,1-Dimeth l~yl4-f(2f~-2-(4-Fluorophenyl)-2-hydroxyethyll-2,2-dimethyl-(4S~-oxazolidinecarboxylate, and 1,1-Dimeth~thyl 4-[(2R)-2-(4-Fluorophenyl)-2-~drox~ethyl]-2,2-dimethyl-((4S~-3-oxazolidinecarboxylate ~o A stirred solution of 1,1-dimethylethyl 2,2-dimethyl-4-[(4S)-2-oxoethyl)-3-oxazolidinecarboxylate (3.0 g) in THF (20 ml) under nitrogen was treated at 0 °C with 4-flurophenylmagnesium bromide (2M in ether, 8.32m1) and stirred at 0 °C
for 1h. The solution was quenched with saturated ammonium chloride solution and extracted with ether. The washed and dried (MgS04) extracts were evaporated and the residue was is purified by chromatography (silica, ether/isohexane as eluent) to give the sub-title compound 1,1-dimethylethyl4-[(2S~-2-(4-fluorophenyl)-2-hydroxyethyl]-2,2-dimethyl-(4,5~-3-oxazolidinecarboxylate as a white solid ( 1.62g).
'H NMR 300MHz (d4-MeOH) 7.40-7.35 (2H, m), 7.10-7.04 (2H, m), 4.72-4.61 (1H, m), zo 4.02-3.74 (3H, m), 2.05-1.87 (2H, m), 1.55-1.41 (15H, m).
Further elution gave the second sub-title compound 1,1-dimethylethyl 4-[(2R)-2-(2-fluorophenyl)-2-hydroxyethyl]-2,2-dimethyl-(4S)-3-oxazolidinecarboxylate as a white solid ( 1.21 g).
2s ~H NMR 300MHz (d4-MeOH) 7.39 (2H, m), 7.07 (2H, m), 4.73-4.69 (1H, m), 4.08 (1H, m), 3.92-3.80 (2H, m), 2.15 ( 1 H, m), 1.83 ( 1 H, m), 1.53-1.41 ( 1 SH; m).
b) 2-ff(1R,3S~-3-Amino-1-(4-fluorophenyl)-4-h~ybutylloxy]-6-trifluoromethyl-3-3o pvridinecarbonitrile Ethanedioate A stirred solution of the 2R, 4S isomer from part a) (214mg) and 2-chloro-6-trifluoromethyl-3-pyridinecarbonitrile (130mg) in NMP (3m1) was treated with sodium hydride (60% dispersion in oil, 30mg), stirred overnight and evaporated. The residue was taken up in ether, washed, dried (MgS04) and evaporated. The residue was purified by s chromatography (silica, ether/isohexane as eluent) to give an oil that was taken up in methanol (5m1), treated with 4M HCl in dioxane, stirred for 2h and evaporated.
The residues were purified by preparative reversed phase HPLC on a 19 x 50 mm Xterra C8 5 micron column using 10 to 80% acetonitrile in 2% aqueous 0.880 ammonia solution over 5 min at 20 ml/min. UV detection by DAD. The free base was taken up in ether/
ethanol ~o mixture, treated with a solution of oxalic acid in ethanol and evaporated.
The residue was triturated with ether and residue was dried to give the title compound as a cream powder (85 mg), M.p. 109-114 °C.
MS APCI +ve m/z 370 [M+H]+.
is 'H NMR 300MHz (d4-MeOH) 8.34 (1H, d), 7.56-7.50 (3H, m), 7.13-7.09 (2H, m), 6.35-6.31 ( 1 H, m), 3.85-3.81 ( 1 H, m), 3.75-3.71 ( 1 H, m), 3.53-3.47 ( 1 H, m), 2.53-2.45 ( 1 H, m), 2.34-2.27 ( 1 H, m).
Example 37 zo 2-(2,S'7-Amino-4-(4R)-(3-fluorophenyl)-4-f (4-methoxy-2-nitrophenyl)thiolbutan-1-of a) 1 1-Dimeth 1y ethyl 4-[(2S1-2~3-fluorophenyl)-2-hydrox~ethyll-2,2-dimethyl-3-(4S~-oxazolidinecarbox~late zs T'he sub-title compound was prepared from 3-fluorophenylmagnesium bromide [from 3-fluorobromobenzene (2.91g), magnesium (485mg) and THF (20m1)] and l,l-dimethylethyl 2,2-dimethyl-4-[(4S)-2-oxoethyl)-3-oxazolidinecarboxylate (3.0 g) by the method of Example 36, step a) to give a water-white oil (2.06g).
30 ~H NMR 300MHz (d4-MeOH) 7.39-7.30 (1H, m), 7.18-7.09 (2H, m), 7.02-6.94 (1H, m), 4.75-4.63 (1H, m), 4.02-4.00 (2H, m), 3.76-3.72 (1H, m), 2.02-1.85 (2H, m), 1.55-1.42 (15H, m).

b) 1,1-Dimethyleth~2-(benzoylthio)-2L2R)~3-fluorophenyl)ethyll-2,2-dimeth 345'7-ozolidinecarbox~ate A stirred solution of triphenylphosphine (8.76g) in THF (100m1) under nitrogen was s treated dropwise at 0 °C with DIAD (6.75g), stirred for 30min, treated with a mixture of thiobenzoic acid (4.61g) and the alcohol from part a) (5.67g), stirred overnight and evaporated. The residue was filtered through a pad of silica with dichloromethane/methanol and the filtrate was evaporated. The residue was digested with ether/isohexane and the supernatant was decanted off and evaporated. The residue was io purified by chromatography (silica,.dichloromethane/ isohexane) to give the sub-title .
compound as a yellow oil (4.8g) that was used directly for the next stage.
c) l , l -Dimethylethyl 4-f ~,2R)-2-(3-Fluorophenyl)-2-mercaptoethyll-2,2-dimethy~4S1-3-oxazolidinecarboxylate is A mixture of the product from step c) (4.8 g) and 7M methanolic ammonia was stirred for 6 h and evaporated to give the sub-title compound as a gum which was taken up in NMP
(86 ml) and used directly for the next stage.
MS APCI +ve m/z 356 [M+H]+.
zo d, 2-(2S)-Amino-4-(3-fluorophen~)-4-(4R)-[~4-methoxy-2-nitrophenyl)thio]butan-1-of A mixture of caesium carbonate (717 mg) and 4-chloro-3-nitroanisole (0.2 mmol) was treated with the solution of the thiol from step d) (2m1) and stirred overnight. The mixture was diluted with water and extracted with methylene chloride. The washed and dried zs (MgS04) extracts were evaporated and the residue was purified by chromatography (silica, ether/isohexane) to give an oil that was taken up in methanol (2m1), treated with 4M HCl in dioxan (5 ml), stirred for 30 min and evaporated. The residue were purified by preparative reversed phase HPLC on a 19 x 50 mm Xterra C8 5 micron column using 10 to 60% acetonitrile in 2% aqueous 0.880 ammonia solution over 6 min at 20 ml/min.
UV
3o detection by DAD to give the title compound as a yellow oil (5 mg).
MS APCI +ve "'/z 367 [M+H]+.

'H NMR 300MHz (d4-MeOH) 7.44-7.38 (2H, m), 7.31-7.24 (1H, m), 7.16-7.05 (3H, m), 6.98-6.91 (1H, m), 4.65-4.60 (1H, m), 3.83 (3H, s), 3.50-3.35 (2H, m), 2.77-2.69 (1H, m), 2.16-2.06 ( 1 H, m), 1.96-1.87 ( 1 H, m).
s Example 38 2(2S)-Amino-4(4R)-(3-fluorophenyl~((4-chloro-2-nitrophenyl)thiolbutan-1-of The title compound was prepared from 1-bromo-4-chloro-2-nitrobezene and the thiol from io Example 3, step c) (2 ml) by the method of Example 37 step d) as a yellow oil (14 mg).
MS APCI +ve m/z 371 [M+H~+.
' H NMR 300MHz (d4-MeOH) 8.04-8.03 ( 1 H, m),' 7.63 ( 1 H, d), 7.54 ( 1 H, dd), 7.36-7.19 (3H, m), 7.01-6.94 ( 1 H, m), 4.83-4.79 ( 1 H, m), 3.46-3.34 (2H, m), 2.67-2.59 ( 1 H, m), ~ s 2.17-2.06 ( 1 H, m), 1.97-1. 87 ( 1 H, m).
Example 39 225)-Amino-4(4R)-(3-fluorophenJrl)-4-f (5-amino-4-chloro-2-nitrophenyl)thiolbutan-1-of The title compound was prepared from 1-bromo-4-chloro-2-nitrobezene and the thiol from Example 37, step c) (2 ml) by the method of Example 37, step d) as a yellow oil (14 mg).
MS APCI +ve m/z 386 [M+H]+.
zs 'H NMR 300MHz (d4-MeOH) 8.13 (1H, s), 7.37-7.26 (3H, m), 7.03-6.96 (1H, m), 6.83 ( 1 H, s), 4.71-4.66 ( 1 H, m), 3 .47-3.34 (2H, m), 2.69-2.61 ( 1 H, m), 2.14-1.90 (2H, m).
Example 40 2(2S)-Amino-4(4R)-(3-fluoro~henyl)-4-f(4-hydrox~hyl)-2-nitrophenyl)thiolbutan-1-of The title compound was prepared from 1-bromo-4-chloro-2-nitrobezene and the product from Example 37, step c) (2 ml) by the method of Example 37, step d) as a yellow oil (12 mg).
s MS APCI +ve m/z 367 [M+H]+.
~ H NMR 300MHz (d4-MeOH) 7.97 ( 1 H, d), 7.61 ( 1 H, d), 7.49 ( 1 H, dd), 7.31-7.19 (3 H, m), 6.98-6.91 (1 H, m), 4.86-4.78 ( 1 H, m), 4.61 (2H, s), 3.46-3.33 (2H, m), 2.68-2.60 ( 1 H, in), 2.13-2.04 (1H, m), 1.97-1.87 (1H, m).
~o Example 41 ~2S)-Amino-4(~4R)-(3-fluorophenyl)-4- f (4-fluoro-2-nitrophenyl)thiolbutan-1-of The title compound was prepared from 1-chloro-4-fluoro-2-nitrobezene and the thiol from is Example 37 step c) by the method of Example 37 step d).
MS APCI +ve m/z 355 [M+H]+.
~ H NMR 300MHz (d4-MeOH) 7.79-7.74 ( 1 H, m), 7.68-7.61 ( 1 H, m), 7.39-7.26 (2H, m), 7.24-7.14 (2H, m), 7.01-6.93 ( 1 H, m), 4.79-4.72 ( 1 H, m), 3.47-3.3 S (2H, m), 2.69-2.60 zo ( 1 H, m), 2.16-2.05 ( 1 H, m), 1.96-1.86 ( 1 H, m).
Example 42 21~2S)-Amino-4(4R)-(3-fluorophenyl)-4-f (3,5-dichloro-2-pyridyl)thiolbutan-1-of zs The title compound was prepared from 2,3,5-trichloropyridine and the thiol from Example 37 step c) (2m1) by the method of Example 37 step d) as a water-white oil (25 mg).
MS APCI +ve m/z 361 [M+H]+, 'H NMR 300MHz (d4-MeOH) 8.43 (1H, d), 7.82 (1H, d), 7.37-7.23 (3H, m), 7.02-6.95 ( 1 H, m), 5.28-5.21 ( 1 H, m), 3.48-3.34 (2H, m), 2.71-2.63 ( 1 H, m), 2.26-2.16 ( 1 H, m), 2.08-1.99 ( 1 H, m).
s Exarilple 43 4-ff(1R,3S)-3-Amino-4-hydroxy-1-Qhenylbut~]thiol-3-chlorobenzonitrile Ethanedioate a) 1,1-Dimethyleth~(4,5'7-4-[~2R)-2-f (2-chloro-4-cyanophenyll)thiol-2-phenylethyll-2,2-io dimethyl-3-oxazolidinecarboxylate The sub-title compound (320 mg) was prepared by the method of Example 3 step a) using the product from Example 1 step b)~ and 3-chloro-4-fluorobenzonitrile.
MS APCI +ve m/z 3473/5 (M+H+) is 'H NMR 400MHz (db-DMSO (90°C)) 7.87 (1H, d), 7.45-7.62 (4H, m), 7.23-7.34 (3H, m), 4.70 ( 1 H, m), 4.04 ( 1 H,m), 3.78 ( 1 H,m), 3.65 ( 1 H, m), 2.15 ( 1 H, m), 2.06 ( 1 H, m), 1.46 (9H, s), 1.43 (3H,s), 1.39 (3H, s).
b) 4-f f ( 1 R,3 S)-3-Amino-4-hydroxy-1 phenylbutyllthio]-3-chlorobenzonitrile Ethanedioate 2o The title compound (175 mg) was prepared as a white solid (M.p. 142 - 144 °C) by the method of Example 4 step b) using the product from step a).
MS APCI +ve m/z 333/5 (M+H+) 'H NMR 400MHz (d6-DMSO) 8.02 ( 1 H, s), 7.75 ( 1 H, d), 7.61 ( 1 H, d), 7.52 (2H, m), Zs 7.25-7.4 (3H, m), 5.00 ( 1 H, m), 3.50 ( 1 H, m), 3.39 ( 1 H, m), 2.96 ( 1 H, t), 2.10-2.30 (2H, m).
Example 44 4-Chloro-2-f f ( lR,3f~-3-(ethylamino)-4-hydroxy-1-(2-thiazolyl)butyl]oxy]-5-fluoro-benzonitrile ethanedioate salt To a solution of the product from Example 8 step c) (140 mg) in ethanol (4 ml) was added s acetaldehyde (35 p1) and the reaction stirred for 16 h. After cooling to 0 °C, sodium borohydride (77 mg) was added and the reaction stirred for 30 min. Water (0.5 ml) was added and the mixture was diluted with ethyl acetate and filtered. The solution was dried (MgS04) and evaporated. Purification by reversed phase HPLC, neutralisation of relevant fractions and addition of ethanedioic acid (1 eq) gave the title compound:
Recrystallisation io from ethyl acetate / diethyl ether gave a white solid. M.p. 55-80 °C.
MS (APCI+ve) m/z 370 ~M(+H)]+.
H 400MHz (CD30D) 7.87 ( 1 H, d), 7.70 (2H, m), 7.40 ( 1 H, d), 6.05 ( 1 H, dd), 3 .92 ( 1 H, dd), 3.80 ( 1 H, dd), 3.51 ( 1 H, m), 3.16 (2H, m), 2.54 (2H, m), 1.33 (3H, t).
is Example 45 2-ff(1R,3.S~-3-Amino-4-hydroxy-1-(5-thiazolyl)butylloxy]-5-fluoro-benzonitrile (2~-2-butenedioate zo a) 1 1-Dimethylethyl (4S1-4-f(2R)-2-(2-chloro-5-thiazolyl)-2-h d~y_ethyll-2,2-dimethyl-3-oxazolidinecarboxylate and 1,1-dimeth l~yl (4S~-4-f(2S~-2-(2-chloro-5-thiazolyl h dy roxyethyll-2,2-dimethyl-3-oxazolidinecarboxylate Butyl lithium (1.6 M in hexanes, 4.26 ml) was added dropwise to a solution of zs diisopropylamine ( 1.59 ml) in THF (20 ml) at -78 °C under a nitrogen atmosphere. After 15 minutes at -78 °C a solution of 2-chlorothiazole (900 mg) in THF (10 ml) was added dropwise and the reaction mixture was stirred cold for 15 minutes. A solution of 1,1-dimethylethyl (4,5~-2,2-dimethyl-4-(2-oxoethyl)-3-oxazolidinecarboxylate ( 1.82 g) in THF
(10 ml) was then added over 5 minutes. After the addition was complete the cooling was 3o removed and the mixture was stirred for 30 minutes. The reaction mixture was poured into water and the products extracted with diethyl_ether. The combined extracts were dried (MgS04), filtered and.evaporated under vacuo. Purification by chromatography (silica, 50% isohexane/diethyl ether as eluent) gave the (4S, 2S) sub-title compound (500 mg) as a colourless oil.
~ H NMR 400MHz (CDC13) 7.34 ( 1 H, s), 5.47 ( 1 H, d), 4.80 ( 1 H, d), 4.32 ( 1 H, m), 4.03 ( 1 H, m), 3.73 ( 1 H, d), 2.09 ( 1 H, m), 1.89 ( 1 H, m), 1.53 ( 1 SH, m).
Further elution gave the (4S, 2R) sub-title compound (380 mg) as a colourless oil.
~o I H NMR 400MHz (CDC13) 7.3 7 ( 1 H, s), 5.01 ( 1 H, m), 4.73 ( 1 H, br s), 4.18 ( 1 H, br s), 4.05 ( 1 H, m), 3.73 ( 1 H, br d), 2.18 (2H, br d), 1.48 ( 1 SH, m).
b) 1,1-Dimeth l~yl (4S)-4-~(2R)-2-h~oxy-2-(5-thiazolyl)eth~]-2,2-dimeth~
is 3-oxazolidinecarboxylate 10% Palladium on charcoal was added to a solution of the product from step a) (380 mg) and sodium acetate (129 mg) in ethanol (15 ml). The reaction mixture was stirred under 5 atmospheres of hydrogen for 16 h. The mixture was filtered and evaporated. The residue was then dissolved in dichloromethane, re-filtered and evaporated to give the sub-title 2o compound (235 mg) as a colourless oil.
1 H NMR 400MHz (CDCl3) 8.73 ( 1 H, br s), 7.76 ( 1 H, s), 5.12 ( 1 H, m), 4.22 ( 1 H, m), 4.04 ( 1 H, m), 3.82 ( 1 H, m), 2.22 (2H, m), 1.48 ( 1 SH, s).
Zs c) 1 1-Dimethyleth~l (4S) 4-f(2R)-2-(2-cyano-4-fluorophenoxy)-2-(5-thiazolyl)ethyl]-2,2-dimethyl-3-oxazolidinecarboxylate Caesium carbonate (466 mg) was added to a solution of the product from step b) (235 mg) and 2,5-difluorobenzonitrile (100 mg) in DMF (15 ml). The reaction mixture was then stirred at room temperature for 3 days. The reaction temperature was then increased to 55-30 60 °C for 5 days. After cooling to room temperature the mixture was diluted with water and extracted with ethyl acetate. The organic phase was dried (MgS04), filtered and concentrated in vacaco and the residue was purified by chromatography (silica, isohexane/ethyl acetate as eluent). The sub-title compound (150 mg) was obtained as a colourless oil.
MS APCI +ve m/z 448 ([M(+H)]+).
s d) 2-[[(1R,3.S~-3-Amino-4-h d~roxy-1-(5-thiazolyl)butylloxy~-5-fluoro-benzonitrile (2~-2-butenedioate The title compound was prepared by the method of Example 10 step n) using the product from step c). M.p. 163-165 °C..
~o MS APCI +ve m/z 308 ([M(+H)]+).
I H NMR 400MHz (db-DMS O) 9.11 ( 1 H, s), 8.04 ( 1 H, s)~, 7.73 ( 1 H, m), 7.52 ( 1 H, m), 7.41 ( 1 H, m), 6.47 (2H, s), 6.24 ( 1 H, t), 3.55 ( 1 H, m), 3.46 ( 1 H, m), 3.00 ( 1 H, t), 2.30 ( 1 H, m), 2.17 ( 1 H, m).
is Example 46 2 j[(1R,3,S~-3-Amino-4-methoxy-1-phen l~yllthio]-6-methyl-3-pyridinecarbonitrile ethanedioate zo a) 6-Methyl-2-[[f 1R)-1-phenyl-3-butenyl~thiol-3-pyridinecarbonitrile A mixture of 2-mercapto-6-methyl-3-pyridinecarbonitrile (6.08 g), a-(2-propenyl)-(a',5'~-benzenemethanol (6 g) and triphenylphosphine (13.8 g) was stirred in dry THF
(150 ml) at 0°C. To the mixture was added diisopropyl azodicarboxylate ( 10.4 ml) dropwise over 2s 20 min. The mixture was then allowed to reach ambient temperature and stirred for 17 h.
The reaction mixture was then concentrated to dryness and the residue purified by chromatography (silica isohexane/ethyl acetate 95:5) to afford the sub-title compound as a pale yellow oil (9.58 g).
3o MS APCI +ve '"/z 281 ([M+H]+) b) 2-[[(1R,3R -3,4-Dihydroxy-1=phenYlbutyl)thio]'-6-methyl-3-pyridinecarbonitrile AD-mix (3 (47.89 g) was added to a vigorously stirred mixture of 2-methyl-2-propanol and water (160 ml of each). The mixture was cooled to 0°C and the product from step a) (9.58 g) added dropwise to the mixture as a solution in 2-methyl-2-propanol (20 ml).
After 20 h at 0°C the mixture was extracted with ethyl acetate (3x100 ml) and the organic extracts combined, dried (NazS04) and concentrated to dryness. The mixture was purified by chromatography (silica dichloromethane/7M ammonia in methanol 99:1 to 98:2) to give the sub-title compound (5.39 g). .
MS APCI +ve '~/z 315 ([M+H]+) io 2-f f ( 1R 3R)-4-f f f 1,1-Dimethylethyl)dimethylsilylloxyl-3-h day-1-phenylbutyllthiol-6-methyl-3-pyridinecarbonitrile Chloro-(1,1-dimethylethyl)dimethylsilane (1.54 g) was added to a stirred mixture of the product from step b) (3.2 g) and imidazole (700 mg) in dry THF (75 ml) at 0°C. The ~s mixture was stirred at 0°C for 1 h and at 20 °C for 1 h.
Extra chloro-(1,1-dimethylethyl)dimethylsilane (750 mg) and imidazole (350 mg) was added and stirring continued for a further 3 h. The mixture was concentrated to dryness and the residue dissolved in diethyl ether ( 100 ml) and the solution passed through a pad of silica gel. The ethereal solution was then concentrated to dryness to afford the sub-title (3 g).
zo MS APCI +ve m/z 429 ([M+H]+) d) 2-ff(1R 3R)-4-[[(1 1-Dimethylethy~dimethylsil~]'oxyl-3-f(methylsulfonyl)oxyl-1-phenylbutyllthio]-6-methyl-3=pyridinecarbonitrile zs A solution of the product from step c) (5 g) in dry THF (50 ml) at 0 °C was treated with diisopropylethylamine (2.1 ml) and methanesulphonyl chloride (0.91 ml) and the mixture stirred for 1 h. A further 2 equivalents of diisopropylethylamine and methanesulphonyl chloride were added over the next 3 h to complete the reaction. The solvent was then removed under reduced pressure and the residue dissolved in a mixture of dichloromethane 3o and diethyl ether (200 ml 1:1 ) and the solution passed through a pad of silica gel. The filtrate was collected and combined with further ether washes of the silica gel.
Concentration gave the sub-title compound which was used immediately.

MS APCI +ve m/z 507 ([M+H]+) e) 2-ff(1R,3S~-3-Azido-4-[[(1,1-dimethylethyl)dimethylsilylloxyl-1-phenylbu llthio]-6-s methyl-3-Qyridinecarbonitrile The product from step d) was dissolved in dry DMF (50 ml) and the solution treated with sodium azide ( 1.52 g). The mixture was heated to 90 °C for 4 h then cooled and diluted with water (100 ml). The products were extracted into diethyl ether (2x100 ml) and the combined extracts dried ( MgS04) and concentrated to an oil. The crude product was to purified by chromatography (silica diethyl ether/isohexane 1:4) to give the sub-title compound (4.9 g).
1 H NMR 400MHz (CDCl3) 7.59 ( 1 H, d), 7.43-7.2 (5H, m), 6.86 ( 1 H, d), 5.29 ( 1 H, dd), 3.65-3.54 (2H, m), 3.04 (1H, m), 2.56 (3H,s) 2.25-2.07 (2H, m), 0.83 (9h, s), 0.00(6H, s).
is f) 2-[[(1R;3S1-3-Azido-4-h droxy-1-phenylbutyl]thio,-6-methyl-3-pyridinecarbonitrile The product from step e) in dry THF (50 ml) containing tetrabutylammonium fluoride ( 11 ml, lmolar solution in THF) was stirred at ambient temperature for 20 h. The mixture was concentrated to dryness and the residue dissolved in a mixture of diethyl ether and zo dichloromethane then passed through a pad of silica gel. The filtrate was concentrated to give the sub-title compound (2.6 g).
MS APCI +ve "'/z 454 ([M+H]+) zs g) 2-ff(1R,3S1-3-Azido-4-~(methylsulfonyl oxyLphenylbutyl]thiol-6-methyl-3-pyridinecarbonitrile An ice cold solution of the product from step f) (0.5 g) and diisopropylethylamine (0.26 ml) in dry THF(20 ml) was treated with methanesulphonyl chloride (0.12 ml).
After the addition was complete the mixture was allowed to reach room temperature and stirred for 1 3o h. More diisopropylethylamine (0.26 ml) and methanesulphonyl chloride (0.12 ml) were added and stirring continued for a further 2 h. The mixture was diluted with water ( 100 ml) and the products extracted into ethyl acetate (2x50 ml). The combined organic extracts were dried ( MgS04) and concentrated to an oil. The crude product was purified by chromatography(silica, diethyl ether/isohexane 1:1). The sub-title compound was isolated as an oil (630 mg).
s MS APCI +ve m/z 418 ([M+H]+) h) 2-[(3-Azido-4-methoxy-1-phenylbutyl)thio]-6-meth~pyridinecarbonitrile A solution of the sulfonate ester from step g) (0.9 g) in methanol (50 ml) was treated with sodium methoxide (1 ml 25wt/v solution in methanol) and the mixture refluxed for 20 h.
~o The mixture was then concentrated to low volume and treated with 10%
aqueous citric acid (20 ml). The products were extracted into diethyl ether ( 100 ml) and the extract dried MgS04) and concentrated. The crude oil was purified by chromatography (silica, diethyl ether/isohexane 1:4) to afford the sub-title compound as an amber oil (200 mg).
is MS APCI +ve m/z 354 ([M+H]+).
i) 2-[[(1R,3,5~-3-Amino-4-methoxy-1-phenylbutyllthiol-6-methyl-3-pyridinecarbonitrile A solution of azide 46 g (198 mg) and triphenylphosphine in wet THF (10 ml +
0.2 ml water) was stirred and heated under reflux for 3 h. The mixture was then concentrated, and zo the residue purified by chromatography (silica, dichloromethane/7M ammonia in methanol 95:5) to afford the free base ( 180 mg). The ethanedioic acid salt was prepared by addition of 1 equivalent of ethanedioic acid in acetonitrile to the free base affording a cream coloured solid (180 mg).
2s MS APCI +ve m/z 328 ([M+H]+) 'H 400MHz (db-DMSO) 8.08 (1H, d), 7.51-7.19 6H, m), 5.31 (1H, t), 3.47-3.35 (2H, m), 3.21-3.17 (4H, m), 2.6 (3H, s), 2.33 (2H, t).
Example 47 2-((( 1 R,3,S'7-3-Amino-4-hydroxy-4-methyl-1-phenylpentylloxyl-4-chloro-5-fluoro benzonitrile ethanedioate a) 1 1-Dimethylethyl (4S) 4-((2R)-2-hydroxy-2-phenylethyll-2,2,5,5-tetramethyl-s oxazolidinecarbox~late A solution of 1,1-dimethylethyl (4S~- 2,2,5,5-tetramethyl-4-(2-oxoethyl)-3-oxazolidinecarboxylate (4.6 g) in dry THF (50 ml) and under an atmosphere of nitrogen was treated at 0°C with phenylmagnesium bromide (lmolar solution in THF
22 ml). After the addition was complete the reaction was allowed to warm to 20°C, and stirred for 0.5 h.
~o The reaction mixture was quenched with aqueous citric acid (150 ml, 10%
w/v), and the products extracted into ethyl acetate (2x75 ml). The combined organic extracts were dried (MgS04) and concentrated to a gum. The mixture of diastereomers was separated by chromatography (silica, isohexane/diethyl ether). The title compound was isolated as a colourless solid (1.3 g).
is ~ H 400MHz (d6-DMSO) 7.3 5-7.20 (5H, m), 5.19 ( 1 H, d), 4.63-4.59 ( 1 H, m), 3.93 ( 1 H, m), 1.9-1.7 (2H, m), 1.50 (3H, s), 1.44 (9H, s), 1.29 (3H, s), 1.26 (3H, s), 1.24 (3H, s).
b) 1 1-Dimethylethyl (4514-[(2R)-2-(S-chloro-2-cyano-4-fluorophenoxy)-2-phenylethyll-zo 2 2,5,5-tetramethyl-3-oxazolidinecarboxylate The sub-title compound was prepared according to the procedure described in Example 8 step b), using the product of step a).
MS APCI +ve "'/z 403 ([M+H-boc~+) 2s c) 2-(((1R 3,5~-3-Amino-4-hydroxy-4-methyl-1-phenylpentylloxy]-4-chloro-5-fluoro benzonitrile ethanedioate The title compound was prepared from the compound from step b) by the method of Example 8 step c). M.p 80°C.

IH 400MHz (d6-DMSO) 7.62 ( 1 H, d), 7.49-7.34 (5H, m), 7.17 ( 1 H, d), 5.67 ( 1 H, dd), 3.24 (1H, dd), 2.38-2.25 (2H, m), 1.26 (3H, s), 1.21 (3H, s).
MS APCI +ve "'/z 363 ([M+H]+).
s Example 48 2-[[( 1 S,3S)-3-Amino-4-hydroxy-1-pro~~butylloxy]-4-chloro-5-fluorobenzonitrile ethanedioate to a) 1,1-Dimethylethyl (4S) 4-f (2S)-2-hydroxypentyll-2,2-dimethyl-3-oxazolidinecarboxylate The sub-title compound was prepared by the method of Example 47 step a), but using propylmagnesium chloride and 1,1-dimethylethyl (4S)-2,2-dimethyl-4-(2-oxoethyl)-3-oxazolidinecarboxylate.
IS
MS APCI +ve '"/z 188 ([M+H-boc]+) b) 1,1-Dimethylethyl (4S) 4-~(2S)-2-(5-chloro-2-cyano-4-fluorophenoxy)pentyl]-2,2-dimethyl-3-oxazolidinecarboxylate.
zo The sub-title compound was prepared by the method of Example 8 step b), using the product of step a) in dry THF.
MS APCI +ve m/z 341 ([M+H-boc]+).
is c 2-ff(1S,3S)-3-Amino-4-h~y-1-pro~ylbu lloxyl-4-chloro-5-fluorobenzonitrile ethanedioate The title compound was prepared according to the procedure described for the product from Example 8 step c). M.p. 171-2°C
3o MS APCI +ve "'/z 301 ([M+H]+) 1 H 3 OOMHz (db-DMSO) 8.02 ( 1 H, d), 7.66 ( 1 H, d), 4.79 ( 1 H, m), 3 .67-3 .61 ( 1 H, m), 3.48-3.42 ( 1 H, m), 3.2 ( 1 H, m), 1.92 (2H, t), 1.66-1.56 (2H, m), 1.5-1.2 (2H, m), 0.89 (3H, t).
Example 49 s 2-f f ( l,S~-1-f (2,S'7-2-Amino-3-hydroxypropyllpentyllthio]-6-methyl-3-gyridinecarbonitrile ethanedioate a) 1,1-Dimethylethyl (4S1- 4-[(2R)-2-h d~yhexyll-2,2-dimethyl-3-io oxazolidinecarbox The sub-title compound was prepared in a similar procedure to that described for the compound from Example 47 step a), but using butylmagnesium chloride and 1,1-dimethylethyl (4S~-2,2-dimethyl-4-(2-oxoethyl)-3-oxazolidinecarboxylate.
is 'H 300MHz (d6-DMSO) 4.53(1H, d), 4.28-4.22 (1H, m), 4.00 (1H, dd), 3.66 (1H, d), 3.55-3 .42 ( 1 H, m), 1. 8-1.71 ( 1 H, m), 1. 5-1.3 (21 H, m), 0. 90 (3 H, t).
b) 1,1-Dimethylethyl (4S1-4-f(2f~-2-(benzoylthio)hexy~-2,2-dimethyl-3-oxazolidinecarboxylate Zo The sub-title compound was prepared by the method of Example 1 step b), but using the product from Example 49 step a).
MS APCI +ve m/z 322 ([M+H-boc]+) is c) 1,1-Dimethylethyl (4S~ 4-[(2 -2-f (3-cyano-6-methyl-2-p ~~ndin~ thiolhex 1v_1-2-2-dimethyl-3-oxazolidinecarboxylate The sub-title compound was prepared by the method of Example 17 step b), but using the product from Example 49 step b).
3o MS APCI +ve m/z 434 ([M+H]+).

dl 2-f f ( 1 S1-1-f (2S1-2-Amino-3-hvdroxvnropvllpentvllthiol-6-methyl-3-pvridinecarbonitrile ethanedioate The title compound was prepared by the method of Example 8 step c) using the product of step c).
MS APCI +ve m/z 294 ([M+H]+).
1 H 400MHz (d6-DMSO) 8.09 ( 1 H, d), 7.2 ( 1 H, d), 4.22 ( 1 H, br s), 3.5-3.8 (2H, m), 3.2 (1H, br s), 2.52 (3H, s), 1.5-2.2 (4H, m), 0.93 (4H,d), 0.88 (3H, t).
~o Example 50 2-[[( 1 S,3S)-3-Amino-4-hydroxy-1-(2-methylpropyl)butyllthio]-6-methyl-3-pyridinecarbonitrile ethanedioate is a) 1,1-Dimeth~ethyl (4S)-4-f(2R)-2-hydroxy-4-methylpentyll-2,2-dimethyl-3-oxazolidinecarboxylate The sub-title compound was prepared by the method of Example 47 step a) but using isobutylmagnesium chloride and 1,1-dimethylethyl (4S)-2,2-dimethyl-4-(2-oxoethyl)-3-oxazolidinecarboxylate.
MS APCI +ve m/z 202 ([M+H-boc]+).
b) 1,1-Dimethylethyl (4S)-4-[~2S)-2-(benzoy lthio -4-methvlpentyll-2,2-dimethyl-3-oxazolidinecarboxylate zs The sub-title compound was prepared by the method of Example 1 step b), but using the product from step a).
MS APCI +ve m/z 322 ((M+H-boc]+).
3o c) 1,1-Dimethylethyl (4S)-4-((2S)-2-j(3-cyano-6-methyl-2-pyridinyl)thiol-4-methylpentyll-2,2-dimethyl-3-oxazolidinecarboxylate The sub-title compound was prepared by the method of Example 17 step b), but using the product from step b).
MS APCI +ve m/z 434 ([M+H]+) s d) 2-f f ( 1 S 3S~-3-Amino-4-hydroxy-1-(2-methylpropyl)butyllthiol-6-methyl-3-pyridinecarbonitrile ethanedioate The title compound was prepared by the method of Example 8 step c), but using the ~o product from step c).
MS APCI +ve m/z 322 ([M+H]+).
1H 400MHz (DMSO-d~) 8.1 ( 1 H, d), 7.2 ( 1 H, d), 4.2-4.1 ( 1 H, m), 3.7-3.5 (2H, m), 3.2 (1H, m), 2.52 (3H, s), 2.1-2 (1H, m), 1.73-1.7 (2H, m), 1.45-1.24 (4H, m), 0.86 (3H, t).
is Example 51 2 j[(3S)-3-Amino-4-hydroxy-1-(S-isoxazolyl)butyllthio]-6-methyl-3-pyridinecarbonitrile (~-butenedioate zo a 4S)-4-~2-(5-Isoxazolyl)-2-oxoethyl]-2-oxazolidinone The sub-title compound was prepared by the method of Example 2 step a) using S-isoxazolecarbonyl chloride.
zs 1H NMR (d6-DMSO) 8 8.84 (1H, d), 7.72 (1H, d), 4.49 (1H, t), 4.37 (1H, t), 4.24 (1H, quintet), 4.06 ( 1 H, dd), 3.92-3.74 (2H, t) b P4S)-4-f2-H~droxy-2-(5-isoxazolyl ethyll-2-oxazolidinone The sub-title compound was prepared by the method of Example 2 step b) using the 3o product of step a).

' H NMR (d6-DMSO) 8.49 ( 1 H, t), 7.83 & 7.65 ( 1 H, s), 6.37 ( 1 H, dd), 5.90 ( 1 H, dd), 4.87 ( 1 H, dd), 4.43-4.31 ( 1 H, m), 4.10-3.72 (2H, m), 1.99-1.85 (2H, m) c) (4S~-4-[2-(Benzoylthio)-2-(5-isoxazolyl~lethyl]-2-oxazolidinone s The sub-title compound was prepared by the method of Example 2 step c) using the product of step b).
MS APCI +ve m/z 318 [M+H]+.
io d) 2-f[1-(5-Isoxazolyl)-2-f(4S1-2-oxooxazolidinyllethyl]thiol-6-meth pyridinecarbonitrile The sub-title compound was prepared by the method of Example 2 step d) using the product of step c).
is MS APCI +ve m/z 330 [M+H]+.
e) 1,1-Dimethylethy~4,S~-4-f 2-f (3-cyano-6-methyl-2-pyridinyl)thio]-2-(5-isoxazolyl)ethyll-2-oxo-3-oxazolidinecarboxylate The sub-title compound was prepared by the method of Example 2 step e) using the zo product of step d).
'H NMR (CDCl3) 8.22 ( 1 H, ddd), 7.75 ( 1 H, dd), 7.03 ( 1 H, dd), 6.44 & 6.29 ( 1 H,2 x dd), 5.59 & 5.48-5.40 (1H, t & m), 4.56-4.22 (3H, m), 2.65-2.54 (5H, m), 1.62-1.48 (9H, m) 2s ~ 1,1-Dimethylethyl ~(1,S'7-3-L(3-c~ano-6-meth~pyridinyl)thiol-1-hydroxymethyl)-3-(5-isoxazolyl)propyllcarbamate The sub-title compound was prepared by the method of Example 2 step f) using the product of step e).
3o MS APCI +ve m/z 405 [M+H]+.

~) 2-ff(3S1-3-Amino-4-hydroxy-1-(5-isoxazolyl)butyllthiol-6-methyl-3-p.~ridinecarbonitrile, (E)-butenedioate A solution of the product from step ~ (48 mg) in 4M HCl in dioxane (2 ml) was stirred for 2 h. 2M Potassium carbonate solution was added and the mixture was as extracted with ethyl acetate. The organic extracts were dried (Na2S04), evaporated and purified by chromatography (silica dichloromethane/7M ammonia in methanol as eluent) then converted into the (E)-butenedioate salt by addition of one equivalent of fumaric acid to give the title compound ( l7mg) as a white solid. M.p. 150-2 °C.
to MS APCI +ve m/z 305 [M+H]+
' H NMR (d6-DMSO) 8.51 ( 1 H, d), 8.13 ( 1 H, d), 7.24 ( 1 H, dd), 6.54 ( 1 H, dd), 6.43 (2H, s), 5.69 & 5.62 (1H, 2 x t), 3.57-3.32 (3H, m), 2.97-2.75 (1H, m), 2.60 (3H, s), 2.43-2.01 (2H, m).
is Example 52 2-[[(3S~-3-Amino-4-h~~ 1-(5-isoxazolyl)butyl]oxyl-6-(trifluoromethyl)-3-pyridinecarbonitrile, (E)-butenedioate zo a) 2-f 1-(5-Isoxazolyl)-2-( 4S1-2-oxo-4-oxazolidinyllethoxy]-6-(trifluorometh 1y )-3-pyridinecarbonitrile Caesium carbonate (1.35 g) was added to a solution of the product of Example 51 step b) (330 mg) and 3-chloro-5-(trifluoromethyl)-2-pyridinecarbonitrile (556 mg) in DMF (2 ml) and the mixture was stirred at 20 °C for 1 h. Ammonium chloride solution was added and is the mixture was extracted with ethyl acetate. The organic extracts were dried (MgS04), evaporated and purified by chromatography (silica, isohexane/ethyl acetate as eluent) gave the sub-title compound (258 mg).
H NMR (CDC13) 8.25 ( 1 H, d), 8.1 S ( 1 H, t), 7.47 ( 1 H, t), 6.53 ( 1 H, t), 6.42 ( 1 H, d), 5.78 30 &, 5.64 ( 1 H, 2 x s), 4.66-4.53 ( 1 H, m), 4.29-4.07 (2H, m), 2.68-2.37 (2H, m) b1 1 1-Dimethylethyl (4,51-4-f2-fL3-cyano-6-(trifluoromethyl)-2-p~ridinylloxyl-2-(5-isoxazol l~)ethyll-2-oxo-3-oxazolidinecarbox The sub-title compound was prepared by the method of Example 2 step e) using the product of step a).
s ~ H NMR (CDC13) 8.24 ( 1 H, d), 8.14 ( 1 H, d), 7.46 ( 1 H, d), 6.5 8 ( 1 H, dd), 6.45 ( 1 H, d), 4.57-4.39 (3H, m), 2.88-2.76 (1H, m), 2.68-2.57 (1H, m), 1.57-1.51 (9H, m) io c) 1,1-Dimethylethyl f ( 1,5~-3 jj3-cyano-6-(trifluoromethyl)-2-pyridinyllox (hydroxymethYl;~-3-(5-isoxazol~)propyll-1-carbamate The sub-title compound was prepared by the method of Example 2 step ~ using the product of step b).
is MS APCI +ve m/z 443 [M+H]+
d) 2-[[(3S)-3-Amino-4-hydroxy-1-(5-isoxazolyl)butyl~oxyl-6-(trifluoromethyl)-pyridinecarbonitrile, (E~-butenedioate The title compound was prepared by the method of Example 51, step g) using the product zo of step c) using. M.p. 150-2 °C.
MS APCI +ve m/z 343 [M+H]+
1H NMR (DMSO) 8.63 (1H, d), 8.57 (1H, d), 7.74 (1H, d), 6.60 (1H, d), 6.55 (1H, t), 6.47 (2H, s), 3.64-3.49 (2H, m), 3.17-3.09 ( 1 H, m), 2.38 (2H, t).
zs Example 53 2-ff[3-(3,5~-Amino-4-h day-1-(1R)-(2-thienyl)butylloxy]-4-chloro-5-fluorobenzonitrile Ethanedioate a) 1,1-DimethYlethyl 4-j(2R)-2-Hydroxy-2-(2-thienyl)ethyll-2,2-dimethyl-(4S1-3-oxazolidinecarboxylate The sub-title compound was prepared from 2-bromothiophene (2.71 g), magnesium (485 mg) and 1,1-dimethylethyl 2,2-dimethyl-4-[(45~-2-oxoethyl)-3-oxazolidinecarboxylate (3 s g) in THF (20 ml) by the method of Example 36, part a) to give an oil ( 1.51 g).
1 H NMR 300MHz (d4-MeOH) 7.31 ( 1 H, dd), 7.03-6.95 (2H, m), 5.00-4.95 ( 1 H, m), 4.15-4.04 ( 1 H, m), 3 . 92-3 . 8 6 ( 1 H, m), 3 . 81-3 .69 ( 1 H, m), 2.3 5-2.18 ( 1 H, m), 2.01-1.90 ( 1 H, m), 1.56-1.44 (15H, m).
io b) 2-ff3-(3S~-Amino-4-hydrox -~)-(2-thienyl)bu lloxy]-4-chloro-5-fluorobenzonitrile Ethanedioate The title compound was prepared from the product from step a) (236 mg) and 4-chloro-2,5-difluorobenzonitrile by the method of Example 36, step b) to give a cream powder (38 is mg).
MS APCI +ve m/z 341 [M+H]+.
1H NMR 300MHz (d4-MeOH) 7.63 ( 1 H, d), 7.47 ( 1 H, d), 7.3 8 ( 1 H, d), 7.24 ( 1 H, d), 7.04-7.01 ( 1 H, m), 6.00 ( 1 H,. dd), 3.87 ( 1 H, dd), 3.75-3.69 ( 1 H, m), 3.63-3.55 ( 1 H, m), Zo 2.58-2.48 ( 1 H, m), 2.40-2.31 ( 1 H, m).
Example 54 2-ff3-(3S'7-Amino-4-hydroxy-1(1R)-(3-thienyl but l~loxy]-4-chloro-S-fluorobenzonitrile is Ethanedioate a) 1 1-Dimethylethyl 4-[(2R -wdroxy-2-(3-thienyl)ethyl]'-2,2-dimethyl-(4,5~-3-oxazolidinecarboxy .
The sub-title compound was prepared from 3-bromothiophene (1.09 g), 1,1-dimethylethyl 30 2,2-dimethyl-4-[(4,5~-2-oxoethyl)-3-oxazolidinecarboxylate (3 g) in THF (20 ml), and magnesium dibromide by the method of Example 35, step a) to give a yellow oil (158 mg).

H NMR 3 OOMHz (d4-MeOH) 7.40-7.3 7 ( 1 H, m), 7.28 ( 1 H, s), 7.12 ( 1 H, d), 4. 84-4.79 ( 1 H, m), 4.13-3.97 ( 1 H, m), 3.91-3.83 ( 1 H, m), 3 .77-3.69 ( 1 H, m), 2.31-2.11 ( 1 H, m), 1.97-1.84 (1H, m), 1.56-1.47 (15H, m).

b) 2 j[3(3S)-Amino-4-hydroxy~lR)-(3-thienyl)butylloxyl-4-chloro-S-fluorobenzonitrile Ethanedioate The title compound was prepared from the alcohol prepared in step a) (158 mg) and 4-chloro-2,5-difluorobenzonitrile by the method of Example 36, step b) to give a cream io powder (30 mg) M.p. 111-115 °C.
MS APCI +ve m/z 341 [M+H]+.
1H NMR 300MHz (d4-MeOH) 7.62 ( 1 H, d), 7.51-7.48 (2H, m), 7.25 ( 1 H, d), 7.18-7.16 ( 1 H, m), 5.78-5.75 ( 1 H, m), 3.86 ( 1 H, dd), 3.72-3.67 ( 1 H, m), 3.58-3.53 ( 1 H, m), 2.47-i s 2.40 ( 1 H, m), 2.29-2.23 ( 1 H, m).
Example 55 2-[[( 1R,3S)-3-Amino-4-hydroxy-1-(3-pyridinyl)butyllthiol-4-(trifluoromethyl)benzonitrile 2o dihydrochloride a) 1,1-Dimethylethyl (4S)-4-~(2S)-2-hydroxy-2-(3-Qmdinyl)ethyll-2,2-dimethyl-3-oxazolidinecarboxylate and 1,1-Dimethyleth 1~(4R)-4-[(2S)-2-hydroxy-2-(3-Qyridinyl)ethyl]-2,2-dimethvl-3-oxazolidinecarboxylate 2s The sub-title compounds were prepared by the method of Example 1 step a) using 3-pyridylmagnesium bromide.
Initial elution of the column gave (2S, 4S) sub-title compound as an oil (3.40 g).
3o MS APCI +ve m/z 323 ([M+H]+).

H NMR 400MHz (CDC13) 8.58 ( 1 H, m), 8.49 ( 1 H, d), 7.75 ( 1 H, d), 7.26 ( 1 H, m), 5.19 ( 1 H, m), 4.68 ( 1 H, m), 4.35 ( 1 H, m), 4.03 ( 1 H, m), 3 .67 ( 1 H, d), 2.03 ( 1 H, m), 1.80 ( 1 H, m), 1.62 (3H, s), 1.53 (12H, m).
s Further elution of the column gave (2R, 4,S'~ sub-title compound as a pale yellow oil (2.30 g) MS APCI +ve m/z 323 ([M+H]+) 1H NMR 400MHz (CDCl3) 8.59 ( 1 H, m), 8.51 ( 1 H, d), 7.73 ( 1 H, d), 7.26 ( 1 H, m), 4.83 ~ o ( 1 H, m), 3.80-4.20 (4H, m), 2.07 (2H, m), 1.65 (3H, s), 1.50 ( 12H, m).
b) 1,1-Dimethylethyl (4S1-4-f(2R)-2-(benzo~lthio)-2- 3 pYridinyl)ethyll-2,2-dimethyl-3-oxazolidinecarboxylate The sub-title compound (2.80 g) was prepared by the method of Example 2 step c) using is the (2S,4S) product from step a).
MS APCI +ve m/z 443 (M+H+).
1H NMR 400MHz (CDCl3) 8.68 ( 1 H, d), 8.51 ( 1 H, m), 7.91 (2H, m), 7.72 ( 1 H, m), 7.55 ( 1 H, m), 7.42 (2H, m), 7.26 ( 1 H, m), 4.78 ( 1 H, m), 3.90-4.15 (3 H, m), 2.5 8-2.3 8 ( 1 H, m), Zo 2.13 ( 1 H, m), 1.60-1.40 ( 15H, m).
c) 1 1-Dimethylethyl (4S)-4-[(2R)-2-[[2-cyano-5-(trifluoromethyl)phenyllthiol-2-(3-pyridinyl)ethyll-2,2-dimethyl-3-oxazolidinecarboxylate The sub-title compound ( 180 mg) was prepared by the method of Example 3 step a) using is the product from step b) and 2-fluoro-4-(trifluoromethyl)benzonitrile.
MS APCI +ve '"/z 508 (M+H+) d) 2-ff(1R,3S1-3-Amino-4-hydrox -~-(3-p ~~idinyl)butyl]thiol-4-30 (trifluoromethyl)benzonitrile dihydrochloride The product from step c) ( 175 mg) was stirred with methanol (5 ml) and 4 M
hydrogen chloride in dioxane (5 ml) for 4 h. The reaction mixture was evaporated and the residue recrystallised from ethanol/diethyl ether to give the title compound (120 mg) as a white solid. M.p. 238-40 °C.
s MS APCI +ve m/z 368 [M+H]+.
1H NMR 400MHz (db-DMSO) 8.90 ( 1 H, s), 8.70 ( 1 H, d), 8.40 ( 1 H, m), 8.30 (2H, m), 8.05 (2H, m), 7.78 (2H, m), 5.47 (1H, m), 3.50-3.60 (2H, m), 3.03 (1H, m), 2.40 (2H, m), , 2.30 (1H, m).
io Example 56 2-f[(1R,3S'~ 3-Amino-4-hydroxy-1-(5-p;rrimidyh)butyllthiol-4-chlorobenzonitri1e hydrochloride is a) 1 1-Dimethylethyl 4-[(2,S')-2-hydrox -~-(3-pyridinyl)eth~l-2,2-dimethyl-(4S~-3-oxazolidinecarboxylate and 1,1-Dimethylethyl 4-f(2R)-2-hydroxy-2-(3-pyridinyl)eth 2,2-dimethy~4,S'7-3-oxazolidinecarbox To a stirred solution of 1,1-dimethylethyl (4S~-2,2-dimethyl-4-(2-oxoethyl)-3-zo oxazolidinecarboxylate (4:55 g) and 5-bromopyrimidine (3.00 g) in dry THF
(50 ml) at -78 °C and under nitrogen was added butyllithium (2.5M in hexanes, 7.90 ml) dropwise. The mixture was stirred at -78 °C for 1.5 hours then quenched with saturated ammonium chloride solution and the products extracted into ethyl acetate. The organic extract was dried (MgS04) and concentrated to an oil. The crude mixture ofdiastereomers was purified 2s by chromatography (silica, methanol/dichloromethane as eluent).
Initial elution of the column gave the (2S,4S) sub-title compound as a yellow solid ( 1.08 g).
MS APCI +ve m/z 324 ([M+H]+) H NMR 400MHz (CDC13) 9.13 ( 1 H, s), 8.76 (2H, s), 5.41 ( 1 H, m), 4.67 ( 1 H, m), 4.38 ( 1 H, m), 4.06 ( 1 H, dd), 3.68 ( 1 H, d), 2.04 ( 1 H, m), 1.79 ( 1 H, m), 1.62 (3H, s), 1.55 (3H, s), 1.53 (9H, s).
s Further elution of the column gave the (2R,4S) sub-title compound as a pale yellow oil (540 mg).
MS APCI +ve ~°/z 324 ([M+H]+).
I H NMR 400MHz (CDC13) 9.13 ( 1 H, s), 8.77 (2H, s), 4.87 ( 1 H, m), 4.67 ( 1 H, m), 4.22 ~ o ( 1 H, m), 3.85 ( 1 H, m), 2.15 (2H, m), 1.48-1.60 ( 15 H, m).
b) 1,1-Dimethylethyl~4S)-4-f(2R)-2-(benzoylthio)-2-(5-pyrimidinyl)ethyl]-2,2-dimethyl-3-oxazolidinecarbox The sub-title compound was prepared by the method of Example 2 step c) using the is (2S,4S) product from step a).
MS APCI +ve °'/z 444 (M+H+).
1H NMR 400MHz (CDC13) 9.11 (1H, s), 8.81 (2H, m), 7.90 (2H, d), 7.58 (1H, m), 7.44 (2H, m), 4.76 ( 1 H, m), 3.96 (2H, m), 2.40-2.65 ( 1 H, m), 2.16 ( 1 H, m), 1.45-1.80 ( 16H, m).
c) 1 1-Dimeth~ethyl (4S)-4-f 2R)-2-[(5-chloro-2-cyanophenyl)thio]-2-(5-pyrimidinyl)ethyl-2,2-dimethyl-3-oxazolidinecarbox The sub-title compound (200 mg) was prepared by the method of Example 3 step a) using the product from step b) and 4-chloro-2-fluorobenzonitrile.
zs MS APCI +ve '"/z 475/7 (M+H+).
d) 2-ff(1R 3S)-3-Amino-4-hydroxy-1-Lpyrimidyl)butyllthio]-4-chlorobenzonitrile hydrochloride so The title compound (90 mg) was prepared as a solid (m.p. 120-30 °C) by the method of Example 7 step c) using the product from step c).

MS APCI +ve m/z 335/7 [M+H]+.
'H NMR 400MHz (d6-DMSO) 9.08 (1H, s), 8.85 (2H, s), 8.23 (3H, bs), 7.90 (1H, d), 7.84 ( 1 H, d), 7.56 ( 1 H, dd), 5.24 ( 1 H, m), 3.50-3.75 (2H, m), 3 .01 ( 1 H, m), 2.43 ( 1 H, m), 2.28 s ( 1 H, m).
ExamQle 57 2-[[( 1R,3S)-3-Amino-4-hydroxy-1-1,3-pyridinyl)butyllthiol-4-chloro-5-fluorobenzonitrile io dihydrochloride a~5-Chloro-2-cyano-4-fluorophenyl) dimeth~carbamothioate A solution of phenol (2.00 g), potassium carbonate (1.85 g) and N,N
dimethylthiocarbamate in acetone (30 ml) was heated to reflux for 24 hours.
The mixture is was poured into water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried (MgS04) and evaporated. The residue was purified by chromatography (silica, isohexane/diethyl ether as eluent) to give the sub-title compound as a solid (2.36 g).
zo MS APCI +ve m/z 259/261 [M+H]+.
'H NMR 400MHz (CDCl3) 7.43 (1H, d), 7.36 (1H, d), 3.46 (3H, s), 3.40 (3H, s).
b~S-(5-Chloro-2-cyano-4-fluorophenyl) dimethylcarbamothioate The product from step a) (2.35 g) was heated under reflux under nitrogen in zs dimethylaniline (25 ml) for 4 hours. The mixture was then poured into 2M
HCl solution and extracted with ethyl acetate 3 times. The combined organic layers were washed with brine, dried (MgS04) and evaporated to leave the sub-title compound as a white solid (2.3 g)~
30 ' H NMR 400MHz (CDCl3) 7.73 ( 1 H, d), 7.52 ( 1 H, d), 3.13 (3H, s), 3.06 (3H, s).
c) 4-Chloro-5-fluoro-2-merca~tobenzorlitrile The product from step b) (2.00 g) was dissolved in methanol ( 100 ml) and a solution of sodium hydroxide (1.55 g) in water (50 ml) added. The mixture was heated to reflux under nitrogen for 1.5 hours. After cooling the mixture was evaporated and the residue diluted with water and then washed twice with diethyl ether. The aqueous layer was acidified with s 2M HCl solution and extracted with ethyl acetate twice. The combined organice extracts were washed with brine, dried (MgS04) and evaporated to give the sub-title compound ( 1.45 g).
1H NMR 400MHz (CDCl3) 7.50 ( 1 H, d), 7.40 ( 1 H, d), 4.08 ( 1 H, s).
io dLl ,1-Dimethylethyl (4f~-4-f (2R)-2-f (5-chloro-2-cyano-4-fluorophenyl)thiol-2-(3-pyridinyl)ethyll-2,2-dirriethyl-3-oxazolidinecarboxylate The product from step c) (100 mg) was dissolved in THF (10 ml) and the (2S,4S) product from Example 55 step a) (170 mg) added followed by triphenylphosphine (140 mg) and is diethyl azodicarboxylate (0:10 ml). The mixture was stirred at 20 °C
for 24 hours and then evaporated. The residue was purified by chromatography (silica, diethyl ether as eluent) to give the sub-title compound as an oil (85 mg).
MS APCI +ve m/z 492/494 [M+H]+.
e~2-[f(1R 3Sy-3-Amino-4-hydroxy-1-(3-pyridin lY)butyllthiol-4-chloro-5-fluorobenzonitrile dihydrochloride The title compound (60 mg) was prepared as an off white solid by the method of Example 55 step d) using the product from step d). M.p. 252-S °C.
zs MS APCI +ve m/z 352/4 [M+H]+.
~H NMR 400MHz (db-DMSO) 8.78 (1H, s), 8.67 (1H, d), 8.20 (1H, d), 8.08 (2H, m), 7.72 ( 1 H, dd), 5.21 ( 1 H, t), 3 .61-3.3 7 (2H, m), 3.03 ( 1 H, m), 2.40 ( 1 H, m), 2.25 ( 1 H, m).
- Example 58 2-f [( lR,3f~-3-Amino-4-hydroxy-1-(3-pyridyl)butyllthiol-4-bromobenzonitrile dihydrochloride a) 1,1-Dimethylethyl (4,5~-4-[(2R)-2-f(5-bromo-2-cyanophenyl)thio]-2-(3-pyridinYl)ethyll s 2,2-dimethyl-3-oxazolidinecarboxylate The sub-title compound ( 170 mg) was prepared by the method of Example 3 step a) using the product from Example 55 step b) and 4-bromo-2-fluorobenzonitrile.
MS APCI +ve m/z 520/2 (M+H+).
~o 'H NMR 400MHz (CDCl3) 8.50-8.30 (1H, m), 7.75-7.57 (SH,m), 7.26 (1H, m), 4.50-3.60 (4H, m), 2:60-2.3.0 ( 1 H, m), 2.18 ( 1 H, m), 1.60-1.40 ( 1 SH, m).
b) 2-f f ( 1 R,3 S)-3-Amino-4-hydroxy~3-pyrid~il)butyl]thio]-4-bromobenzonitrile dihydrochloride is The title compound (118 mg) was prepared as a white solid by the method of Example 55 step d) using the product from step a). M.p. 278-280 °C.
MS APCI +ve m/z 380 [M+H]+.
~H NMR 400MHz (d6-DMSO) 8.94 (1H, s), 8.73 (1H, d), 8.42 (1H, d), 8.32 (3H, bs), zo 8.03 ( 1 H, s), 7.84 ( 1 H, dd), 7.74 ( 1 H, d), 7.68 ( 1 H, dd), 5.41 ( 1 H, m), 3.60-3.48 (2H, m), 3.02 ( 1 H, m), 2.43 ( 1 H, m), 2.27 ( 1 H, m).
Example 59 zs 2-j[(1R,3S~-3-Amino-4-hydroxy-1-(2-thiazol~)butylloxyl-5-fluoro-6-methyl-3-~~ridinecarbonitrile hydrochloride a~Bis(1,1~-dimethylethyl) 2-(6-chloro-5-cyano-3-fluoro-2-pyridinyl)propanedioate To a solution ofbis(l,l-dimethylethyl) malonate (1.08 g) in dry DMF (20 ml) was added 3o sodium hydride (200 mg) under nitrogen. The mixture was stirred at 20 °C for 30 minutes then 2,6-dichloro-3-cyano-5-fluoropyridine added. The mixture was stirred for 30 minutes then poured into glacial acetic acid (100 ml) and extracted into ether. The ether layer was dried (MgS04) and evaporated. The residue was purified by chromatography (silica, dichloromethane/isohexane as eluent) to give the sub-title compound as a solid (1.38 g).
MS APCI +ve "'/z 369/371 (M+H+) H NMR 400MHz (CDC13) 7.72 ( 1 H, d), 4.83 ( 1 H, d), 1.50 ( 18H, s).
b) 2-Chloro-5-fluoro-6-methyl-3-pyridinecarbonitrile To the product from step a) ( 1.3 g) was added trifluoroacetic acid (2 ml) and diphenyl ether io (10 g). The mixture was heated under reflux for 10 min. The mixture was dissolved in isohexane, filtered through silica. And the silica was washed with 10%
dichloromethane/isohexane followed.by dichloromethane. The dichloromethane layer was evaporated to leave a solid which was triturated with cold isohexane to give the sub-title compound (510 mg).
is MS APCI +ve ~'/z 169/71 (M+H+) -'H NMR 400MHz (CDCl3) 7.64 (1H, d), 2.59 (3H, s).
c) l,l-Dimethylethyl (4S~-4-[(2R -2-f 3-chloro-5-fluoro-6-methyl-2-pyridinyl)oxyl-2-(2-2o thiazol l~yll-2,2-dimethyl-3-oxazolidinecarboxylate The sub-title compound ( 180 mg) was prepared by the method of Example 8 step b) using the product from step b) and the (2R,4,S~ product from Example 8 step a).
MS APCI +ve m/z 463/5 (M+H+).
2s d) 2-ff(1R,3S~-3-Amino-4-hydroxy-1-(2-thiazol l~butylloxyl5-fluoro-6-methyl-3-Q idinecarbonitrile hydrochloride The title compound (100 mg) was prepared as a white solid by the method of Example 55 step d) using the product from step c). M.p. 148-50 °C.
MS APCI +ve m/z 323 (M+H+).

'H NMR 400MHz (db-DMSO) 8.38 ( 1 H, d), 8.12 (4H, bs), 7.85 ( 1 H, d), 7.78 ( 1 H, d), 6.60 ( 1 H, m), 3.70 ( 1 H, m), 3.59 ( 1 H, m), 3.35 ( 1 H, m), 2.52-2.43 (5H, m).
Example 60 s 4-ff(1R,3S~-3-Amino-1-(3-fluoro-2-thienyl)-4-hydrox b~ty_1]thiol-6-methoxy-3-Qyridinecarbonitrile (E)-butenedioate salt a) 3-Fluoro-2-thio~henecarboxylic acid.
~o The sub-title compound was prepared by the method of reference (OPPI
BRIEFS, 1997, 29, 221-223) to yield the sub-title compound (1.5 g, 40%) as a yellow solid.
M.p. 171-172 °C (lit. 172-173 °C).
'H NMR 300MHz (CDCl3) S 7.52 (1H, dd) and 6.89 (1H, d).
is b) 3-Fluorothio~hene.
The sub-title compound was prepared by the method of reference (Synth. Comm, 1994, 24, 95-101) to yield the sub-title compound (540 mg, 62%) as a clear liquid.
zo 1 H NMR 300MHz (CDCl3) 7.20-7.16 ( 1 H, m), 6.85-6.83 ( 1 H, m) and 6.71-6.69 ( 1 H, m).
c) (4,S'~-1,1-Dimethethyl 4-[(2S~-2-(3-fluoro-2-thienyl)-2-hydroxyethyll-2,2-dimeth oxazolidinecarboxylate.
The sub-title compound was prepared by the method of Example 1 step a) using (4S~-1,1-is dimethylethyl -2,2-dimethyl-4-(2-oxoethyl)-3-oxazolidinecarboxyate and 3-fluoro-2-thienyllithium instead of phenyllithium. Purification by chromatography (silica, 10% ethyl acetate/isohexane as eluent) afforded the sub-title compound (500 mg, 28%) as a pale yellow gum.
3o MS (APCI+ve) m/z 246 [M(+H)]+.

H NMR 300MHz (CDC13) 7.07 ( 1 H, dd), 6.73 ( 1 H, d), 5.23 ( 1 H, d), 5.03-4.93 ( 1 H, m), 4.3 8-4.28 ( 1 H, m), 4.04-3.99 ( 1 H, m), 3.70-3.66 ( 1 H, m), 2.20-2.10 ( 1 H, m), 1.96=1. 86 (1H, m) and 1.55-1.52 (15H, m).
s d) (4,5~-1,1-Dimethylethyl 4-f (2R)-2-(acetylthio)-2-(3-fluoro-2-thienyl)-2-ethyl-2.2-dimethyl-3-oxazolidinecarboxylate.
The sub-title compound was prepared by the method of Example 10 step g) using thioacetic acid and the product of step c) instead of thiobenzoic acid and (4S)-1,1-dimethylethyl 4-[(2f~-2-hydroxy-2-phenylethyl]-2,2-dimethyl-3-oxazolidinecarboxylate.
io Purification by chromatography (silica, 5% ethyl acetate/isohexane as eluent) afforded the sub-title compound (300 mg) as a colourless oil.
MS (APCI+ve) m%z 304 [M(+H)(-Boc)]+.
'H NMR 300MHz (CDCl3) 7.07-7.05 (1H, m), 6.74-6.70 (1H, m), 4.94-4.80 (1H, m), is 4.05-3.80 (3H, m), 2.36-2.30 (4H, m), 2.18-2.08 (1H, m) and 1.57-1.47 (15H, m).
e1 (4S1-1,1-Dimeth l~yl 4-[(2S~-2-[(S-cyano-2-methoxy-4-pyridinyl)thiol-2-(3-fluoro-2-thienyl)ethyll-2,2-dimethyl-3-oxazolidinecarboxyate.
The sub-title compound was prepared by the method of Example 10 step m) using 2o methoxy-4-(methylsulfonyl)-3-pyridinecarbonitrile and (4S~-1,1-dimethylethyl 4-[(2S~-2-(acetylthio)-2-(3-fluoro-2-thienyl)ethyl]-2,2-dimethyl-3-oxazolidinecarboxyate instead of (4,5~-1,1-dimethylethyl 4-[(2,5~-2-(benzoylthio)-2-phenylethyl]-2,2-dimethyl-3-oxazolidinecarboxylate. Purification by chromatography (silica, 10% ethyl acetate/isohexane) afforded the sub-title compound (100 mg) as a clear gum.
2s MS (APCI+ve) m/z 394 [M(+H)(-Boc)]+.
~H NMR 300MHz (CDCl3) 8.32-8.30 (1H, m), 7.14-7.10 (1H, m), 6.74-6.70 (2H, m) 5.06-4.64 ( 1 H, m), 4.18-4.08 ( 1 H, m), 4.00-3.85 (4H, m), 3.78-3.48 ( 1 H, m), 2.56-2.15 (2H, m) and 1.58-1.46 (15H, m).
fl 4-[[(IR,3S1-3-Amino-1-(3-fluoro-2-thienyl)-4-hydrox~t~]thioL6-method-3-wridinecarbonitrile (E)-butenedioate salt The title compound was made by the method of Example 10 step n) to yield the title compound (56 mg) as a white solid. M.p. 177-178 °C
MS (APCI+ve) m/z 354 [M(+H)]+.
s 1H NMR 300MHz (d6-DMSO) 8.59 (1H, s), 7.55-7.52 (1H, m}, 7.02-6.94 (2H, m), 6.47 (2H, s), 5.45-5.39 ( 1 H, m), 3.92 (3H, s), 3.55-3.3 5 ( 1 H, m), 3.00-2.90 ( 1 H, m), 2.70-2.60 ( 1 H, m); 2.20-2.10 ( 1 H, m) and 2.05-1.95 ( 1 H, m).
Example 61 io 2-f f ( 1 R,3 S)-3-Amino-1-(4-chloro-S-thiazolyl)-4-l~droxybutyl]oxyl-4-chloro-fluorobenzonitrile (ELbutenedioate salt a) 2,4-Dichlorothiazole.
is The sub-title compound was prepared by the method of reference (Bull. Chim.
Soc. Fr., 1962, 1735) to yield the sub-title compound (7.16 g) as a white solid. M.p. 41-42 °C (lit.
42-43 °C).
IH NMR 300MHz (CDC13) 7.01 (1H, s).
2o b) (4,S')-1,1-Dimethylethyl 4~(2R)-2-(2,4-dichloro-5-thiazolyl)-2-hydroxyeth 1v 1-2,2-dimethyl-3-oxazolidinecarboxylate.
The sub-title compound was prepared by the method of Example 1 step a) using (4S~-1,1-dimethylethyl ester-2,2-dimethyl-4-(2-oxoethyl)-3-oxazolidinecarboxylic acid and 2,4-2s dichloro-5-thiazolyllithium instead of phenyllithium. Purification by chromatography (silica, 20% ethyl acetate in isohexane as eluent) afforded the sub-title compound (744 mg) as a pale yellow gum.
MS (APCI+ve) m/z 297/299/301 [M(+H)(-Boc)]+.
30 1H NMR 300MHz (CDCl3) 5.08-4.98 ( 1 H, m), 4.16-4.04 (2H, m), 3.84-3.71 ( 1 H, m), 2.32-2.22 (2H, m) and 1.61-1.45 (15H, m).

c~4,S'~-1,1-Dimethylethyl 4 j(2R)-2-(4-chloro-5-thiazolyl)-2-hydroxyethXll-2,2-dimethyl-3-oxazolidinecarboxylate.
To a stirred suspension of palladium on activated charcoal (75 mg) and sodium acetate trihydrate (380 mg,) in MeOH (10 ml) was added a solution of the product from step b) s (740 mg) in MeOH (15 ml). The mixture was subjected to an atmosphere of hydrogen (5 bar) for 72 h. The mixture was filtered and evaporated to dryness. The residue was dissolved in dichloromethane (25 ml), dried (NazS04), filtered and concentrated in vacuo.
Purification by chromatography (silica, 20% ethyl acetate%isohexane as eluent) afforded the sub-title compound (653 mg) as a colourless gum.
io MS (APCI+ve) m/z 363/365 [M(+H)]+.
' H NMR 300MHz (CDCl3) 8.63 ( 1 H, s), 5.20-5.10 ( 1 H, m), 4.18-4.04 (2H, m), 3.91-3.84 ( 1 H, m), 2.27-2.20 (2H, m) and 1.62-1.44 ( 1 SH, m).
is d) (4,5~-1,1-Dimethylethyl 4-((2R)-2-(5-chloro-2-cyano-4-fluorophenoxy)-2-(4-chloro-5-thiazolyl)ethvll-2,2-dimethyl-3-oxazolidinecarboxvlate.
The sub-title compound was prepared by the method of Example 8 step b) using 4-chloro-2,5-difluorobenzonitrile and the product from step b) (650 mg). Purification by chromatography (silica, 20% ethyl acetate/isohexane) afforded the sub-title compound zo ( 190 mg) as a pale green foam.
MS (APCI+ve) m/z 416/418/420 [M(+H)(-Boc)]+.
'H NMR 300MHz (CDCl3) 9.10 (1H, s), 7.87 (1H, d), 7.39 (1H, d) 5.98' (1H, dd), 4.19-4.13 ( 1 H, m), 3.99-3.97 (2H, m), 2.58-2.48 ( 1 H, m), 2.20-2.13 ( 1 H, m) and 1.42-1.40 zs (15H, m).
e~ 2-ff(1R.3,S')-3-Amino-1-(4-chloro-5-thiazolyl)-4-h d~ybutyllthiol-4-chloro-fluorobenzonitrile (E)-butenedioate salt .
The title compound was made by the method of Example 10 step. n) to yield the title 3o compound (136 mg) as a pale yellow solid. M.p. 177-178 °C
MS (APCI+ve) m/z 376/378/380 [M(+H)]+.

'H NMR 300MHz (d6-DMSO) 9.19 (1H, s), 8.03 (1H, d), 7.65 (1H, d), 6.48 (2H, s), 6.17 ( 1 H, t), 3.60-3.48 (2H, m), 3.10-3.06 ( 1 H, m) and 2.37-2.18 (2H, m).
Example 62 s ~-l[(1R,3,S~-3-Amino-4-hydroxy=1-phenylbutyl]thio]-5-riitrobenzonitrile hydrochloride The title compound was prepared by the method of Example 10 step m) & Example step g) using 2-chloro-4-nitro-benzonitrile and the product from Example 10 step g).
~o MS (APCI+ve) m/z 344 [M(+H)]+.
'H 400MHz (DMSO-d6) 8.68 (1H, s), 8.38 (1H, d of d), 8.19 (3H, bs), 7.95 (1H, d), 7.58 (2H, d), 7.39 (2H, m), 7.31 (1H, t), 5.35 (2H, m), 3.2-3.52 (2H m), 2.96 (1H, bs), 2.33 ( 1 H, m), 2.22 ( 1 H, m).
is Example 63 2-ff(1R,3S~-3-Amino-4-h dery-1-phenylbutyllthiol-5-chloro-3-~yridinecarbonitrile-(~~-butenedioate salt zo a) 2,5-Dichloro-3-pyridinecarbonitrile To n-BuLi ( 1.9 ml of a 2.5M solution in hexanes) in EtzO (4 ml), under nitrogen, at -78 °C, was added a solution of 3-bromo-2,5-dichloro-pyridine (1.08 g) in EtzO (4 ml) dropwise and stirred for 1.5 h. Solid 1-cyanoimidazole (0.53 g) was added and the reaction zs stirred for 2 h. After warming to room temperature, water was added and the mixture was extracted with EtzO. The combined organics were washed with brine, dried (NazS04) and evaporated to give a black solid (0.64 g). Purification by chromatography (silica, isohexane/ EtzO as eluent) gave the sub-title compound (0.13 g) as a white solid.
30 ' H NMR 300MHz (CDCl3) 8.56 ( 1 H, d), 7.98 ( 1 H, d).

b) 2-ff(1R,3S)-3-Amino-4-hydroxy-1-phenylbut~llthio~-5-chloro-3-pyridinecarbonitrile-(~-butenedioate salt The title compound was prepared by the method of Example 10 steps m & n) using the products from step a) and Example 10 step g).
s MS (APCI+ve) ~'/z 334 [M(+H)]+.
1H 400MHz (DMSO-d6) 8.80 (1H, d), 8.50 (1H, d),7.50 (2H, d), 7.36 (2H, t), 7.29 (1H, tt), 6.47 (2H, s), 5.32 ( 1 H, dd), 3.44 ( 1 H, dd), 3.35 ( 1 H, dd), 2.79 ( 1 H, m), 2.29 ( 1 H, m), 2.17 ( 1 H, m) io Example 64 ~3-Amino-8-f f 4-amino-2-nitrophenyl)thiol-( X31 S,8 ~R)-benzenebutanol ~ s a) l , l -Dimeth~leth~ 4S) 4-f (2R)-2-f (4-amino-2-nitrophenyl)thiol-2-phenMeth 1 dimethyl-3-oxazolidinecarboxylate The sub-title compound was prepared by the method of Example 10 steps m) using the product from Example 10 step g) and 4-chloro-3-nitroaniline.
zo MS APCI +ve m/z 374 ([M+H-boc]+).
b) Q-Amino-8-[(4-amino-2-nitrophenyl)thiol-yIS,8lR)-benzenebutanol The title compound was prepared by the method of Example 10 step n) using the products from step a).
is MS APCI +ve m/z 334 ([M+H]+).
~ H 400MHz (DMSO-d~/D20) 7.3 S-7.18 (6H, m), 6.98 ( 1 H, d), 6.72 ( 1 H, dd), 4.54 ( 1 H, t), 3.62-3.36 (2H, m), 2.96 ( 1 H, t), 2.18-2.05 (2H, m).
30 Example 65 2-ff(1R,3S)-3-Amino-4-h~drox ~~-l~hen, lybutyllthio)-5-bromo-benzonitrile ethanedioate a) 1 1-Dimethylethyl (4S)-4-f(2R)-2-f(4-bromo-2-cyanophenyl)thio]-2-phenylethyll-2,2-dimethyl-3-oxazolidinecarboxylate s The product of Example 1 step b) (441 mg) was stirred in 7M NH3 in methanol ( 10 ml) at room temperature under nitrogen for 6 h. The mixture was then concentrated in vacuo, the residue dissolved in DMF ( 10, ml) and treated with 5-bromo-2-fluorobenzonitrile (200 mg), followed by caesium carbonate (65.0 mg) under nitrogen. The mixture was stitTed at room temperature for 20 h and then partitioned between ethyl acetate and water. The separated ~o aqueous phase was extracted with ethyl acetate, and the combined organic extracts were washed with brine, and dried (MgS04). The solvent was evaporated and the residue purified by chromatography (silica, 10% ethyl acetate/isohexane) to give the sub-title compound (332 mg, 64%) as a colourless foam oil.
is MS APCI +ve m/z 418 [M-BOC+2H]+.
b) 1,1-Dimethvlethyl ((1S,3R)-3-[~4-bromo-2-cyanophenyl)thio]-1-(hydrox~ethyl~-phen~prop~] carbamate para-Toluenesulfonic acid monohydrate (1 mg) was added to a stirred solution of the 2o product from step a) in methanol (S ml) under nitrogen, and the mixture was stirred at 20 °C for 48 h. The mixture was diluted .with ethyl acetate and washed with 1 M aqueous potassium hydrogensulfate solution, saturated aqueous sodium bicarbonate, brine and then dried (MgS04) and evaporated. The resulting residue was purified by chromatography (silica, 30% ethyl acetate/isohexane) to give the sub-title compound (175 mg, 57%) as a is colourless foam oil.
MS APCI +ve m/z 378 [M-BOC+2H]+.
c) 2-f f ( 1R,3S)-3-Amino-4-hydrox~l~henylbutyllthiol-5-bromo- benzonitrile ethanedioate 3o The product from step b) was deprotected according to the procedure of Example 4 step b) to give the title compound (113 mg, 65%) as a white solid.

MS APCI +ve m/z 378 [M+H]+.
1H NMR 300 MHz (D6-DMSO) 8.11 ( 1 H, d), 7.83 ( 1 H, dd), 7.50 ( 1 H, d), 7.40-7.25 (5H, m), 4.83 ( 1 H, dd), 3. S 2 ( 1 H, dd), 3 .41 ( 1 H, dd), 3.03-2.95 ( 1 H, m), 2.31-2.21 ( 1 H, m), s 2.15-2.05 ( 1 H, m).
Screens io The pharmacological activity of compounds according to the invention was tested in the following screens.
Screen 1 is The activity of compounds of formula (I), or a pharmaceutically acceptable salt, enantiomer or racemate thereof, may be screened for nitric oxide synthase inhibiting activity by a procedure based on that of Forstermann et al., Eur. J. Pharm., 1992, 225, 161-165. Nitric oxide synthase converts 3H-L-arginine into 3H-L-citrulline which can be separated by cation zo exchange chromatography and quantified by liquid scintillation counting.
Enzyme is prepared, after induction, from the cultured murine macrophage cell line J774A-1 (obtained from the laboratories of the Imperial Cancer Research Fund). J774A-1 cells are cultured in Dulbeccos Modified Eagles Medium (DMEM) supplemented with 10%
foetal zs bovine serum, 4 mM L-glutamine and antibiotics ( 100 units/ml penicillin G, 100 mg/ml streptomycin & 0.25 mg/ml amphotericin B). Cells are routinely grown in 225 cm3 flasks containing 35 ml medium kept at 37 °C and in a humidified atmosphere containing 5% COz.
Nitric oxide synthase is produced by cells in response to interferon-g (IFNg) and 30 lipopolysaccharide (LPS). The medium from confluent culture flasks is removed and replaced with 25 ml (per flask) of fresh medium containing 1 mg/ml LPS and 10 units/ml IFNg. After a period of 17-20 hours in culture, harvesting of cells is accomplished by scraping the cell sheet from the flask surface into the culture medium. Cells are collected by centrifugation ( 1000 g for 10 minutes) and lysate prepared by adding to the cell pellet a solution containing 50 mM Tris-HCl (pH 7.5 at 20 °C), 10% (v/v) glycerol, 0.1% (v/v) Triton-X-100, 0.1 mM
dithiothreitol and a cocktail of protease inhibitors comprising leupeptin (2 mg/ml), soya bean trypsin inhibitor (10 mg/ml), aprotinin (5 mg/ml) and phenylmethylsulphonyl fluoride (50 mg/ml).
For the assay, 25 ~,l of substrate cocktail (50 mM Tris-HCl (pH 7.5 at 20 °C), 400 ~M
NADPH, 20 ~M flavin adenine dinucleotide, 20 ~M flavin mononucleotide, 4 ~.M
to tetrahydrobiopterin, 12 ~M z-arginine and 0.025 mCi z-[3H] arginine) is added to wells of a 96 well filter plate (0.45~M pore size) containing 25 ~1 of a solution of test compound in 50 mM Tris-HCI. The reaction is started by adding 50 ~l of cell lysate (prepared as above) and after incubation for 1 hour at room temperature is terminated by addition of 50 ~1 of an aqueous solution of 3 mM nitroarginine and 21 mM EDTA.
IS
Labelled r.-citrulline is separated from labelled L-arginine using Dowex AG-50W. 150 ~l of a 25% aqueous slurry of Dowex 50W (Na+ form) is added to the assay after which the whole is filtered into 96 well plates. 75 ~.l of filtrate is sampled and added to wells of 96 well plates containing solid scintillant. After allowing the samples to dry the L-citrulline is quantified by Zo scintillation counting.
In a typical experiment basal activity is 300 dpm per 75 ~Il sample which is increased to 1900 dpm in the reagent controls. Compound activity is expressed as ICSO (the concentration of drug substance which gives 50% enzyme inhibition in the assay) and aminoguanidine, which zs gives an ICso (50% inhibitory concentration) of 10 ~M, is tested as a standard to verify the procedure. Compounds are tested at a range of concentrations and from the inhibitions obtained ICso values are calculated. Compounds that inhibit the enzyme by at least 25% at 100 ~M are classed as being active and are subjected to at least one retest.
3o In the above screen, the compounds of Examples 1 to 10 were tested and gave ICSO values of less than 10 ~M indicating that they are expected to show useful therapeutic activity.

Screen 2 Recombinant human NO synthases (iNOS, eNOS & nNOS) were expressed in E. coli and lysates were prepared in Hepes buffer (pH 7.4) containing co-factors (FAD, FMN, H4B), protease inhibitors, lysozyme and the detergent, CHAPS. These preparations were used, at suitable dilution, to assess inhibition of the various isoforms. Inhibition of NOS was determined by measuring the formation of L-[3H]citrulline from L-[3H]arginine using an adaptation of the method of Forstermann et a1.9 Enzyme assays were performed in the io presence of 3 ~,M [3H]arginine, 1 mM NADPH and other co-factors required to support NOS activity (FAD, FMN, H4B, calmodulin, Ca2+). Since various NOS inhibitors have been reported to exhibit slow binding kinetics, or to inactivate the enzyme in a time dependent manner, enzyme and inhibitor were pre-incubated for 60 min in the presence of NADPH before addition of arginine to initiate the reaction. Incubations continued for a ~s further 60 min before the assays were quenched and [3H]citrulline separated from unreacted substrate by chromatography on Dowex-SOW resin in a 96-well format.
In the above screen, the compounds of Examples 1 to 65 were tested and gave ICso values of less than 10 ~,M against the iNOS enzyme indicating that they are expected to show useful Zo therapeutic activity.
Screen 3 Compounds also show activity against the human form of induced nitric oxide synthase as is can be demonstrated in the following assay.
The human colorectal carcinoma cell line, DLD-1 (obtained from the European Collection of Animal Cell Culture - cell line number 90102540) was routinely grown in supplemented with 10%(v/v) foetal bovine serum, and 2mM L-glutamine, at 37 °C in 30 5% CO2.

Nitric oxide synthase was induced in cells by addition of medium containing human recombinant gamma-IFN ( 1000 units/ml), TNF-alpha (200 U/ml), IL-6 (200 U/ml) and IL-1-beta (250 U/ml). After incubation for 18 hours at 37 °C, the medium was removed and the cells washed with warm phosphate buffered saline. Cells were incubated for a further 5 hours at 37 °C / 5% C02 in RPMI 1640 containing 100pM L-arginine and 100pM
verapamil-HCl in the presence and absence of test compounds.
Nitrite accumulation was determined by mixing an equal volume of culture media with Griess reagent ( 10 mg/ml sulphanilamide, 1 mg N ( 1-naphthyl)ethylenediamirle in 1 ml io 2.5% (v/v) phosphoric acid). Inhibition in the presence of compounds was calculated relative to the nitrite levels produced by untreated cells. ICso values were estimated from a semi-log plot of b/o inhibition versus concentration of compound.
In this screen the compounds of Examples 1 to 65 gave ICso values of less than 100 p.M, ~s indicating that they are predicted to show useful therapeutic activity.

Claims (25)

CLAIMS:
1. A compound of formula (I) wherein:
X represents H, C1 to 4 alkyl, C1 to 4 alkoxy, halogen, CN, C=CH, NH2, NHCH3, N(CH3)2, NO2,,CH2OH, CHO, COCH3 or NHCHO; said alkyl or alkoxy group being optionally further substituted by one or more fluorine atoms;
Y represents C1 to 4 alkyl, C1 to 4 alkoxy, halogen, CN, C=CH, NO2, CH2OH, CHO, COCH3 or NHCHO; said alkyl or alkoxy group being optionally further substituted by one or more fluorine atoms;
T, U and W independently represent CR7 or N; and each R7 group independently represents H, F or CH3; and when T represents CR7, the group R7 may additionally represent OH, Cl, Br, CN, CH2OH, NO2, NHR13, OR14 or OSO2CH3;
V represents O or S(O)n;
n represents an integer 0, 1 or 2;
R1 represents H or Me.

R2 represents C1 to 4 alkyl, C2 to 4 alkenyl, C2 to 4 alkynyl, C3 to 6 cycloalkyl or a 4 to 8 membered saturated heterocyclic ring incorporating one heteroatom selected from O, S and N; any of said groups being optionally further substituted by C1 to 4 alkyl, C1 to 4 alkoxy, C1 to 4 alkylthio, C3 to 6 cycloalkyl, halogen or phenyl; said phenyl group being optionally further substituted by one or more substituents selected independently from halogen, C1 to 4 alkyl, C1 to 4 alkoxy, CF3, OCF3, CN or NO2;
or R2 represents phenyl or a five or six membered aromatic heterocyclic ring containing 1 to 3 heteroatoms independently selected from O, S and N; said phenyl or aromatic heterocyclic ring being optionally substituted by one or more substituents selected independently from halogen, C1 to 4 alkyl, C1 to 4 alkoxy, OH, CN, NO2 or NR9R10; said alkyl or alkoxy group being optionally further substituted by one or more fluorine atoms; .
R3 represents H, C1 to 4 alkyl or C3 to 6 cycloalkyl; said alkyl group being optionally substituted by C1 to 4 alkoxy, halogen, hydroxy, NR11R12, phenyl or a five or six membered aromatic or saturated heterocyclic ring containing 1 to 3 heteroatoms independently selected from O, S and N; said phenyl or aromatic heterocyclic ring being optionally further substituted by halogen, C1 to 4 alkyl, C1 to 4 alkoxy, CF3, OCF3, CN or NO2.

R4, R5, R6, R9, R10, R11, R12, R13 and R14 independently represent H or C1 to 4 alkyl;
or a pharmaceutically acceptable salt, enantiomer or racemate thereof.
2. A compound of formula (I), according to Claim 1, wherein V represents O.
3. A compound of formula (I), according to Claim 1, wherein V represents S(O)n and n represents 0.
4. A compound of formula (I), according to any one of Claims 1 to 3, wherein X
and Y
independently represent Br, Cl, CH3, CH2F, CHF2, CF3, OCH3 or CN.
5. A compound according to Claim 4 wherein Y represents CN.
6. A compound of formula (I), according to Claim 1, which is:
2-[[(1R,3S)-3-amino-4-hydroxy-1-phenylbutyl]thio]-6-methyl-3-pyridinecarbonitrile;
2-[[(3S)-3-amino-4-hydroxy-1-(3-isoxazolyl)butyl]thio]-6-methyl-3-pyridinecarbonitrile;
4-[[(1R,3S)-3-amino-4-hydroxy-1-phenylbutyl]thio]-6-methyl-3-pyridinecarbonitrile;
3-[[(1R,3S)-3-amino-4-hydroxy-1-phenylbutyl]thio]-5-(trifluoromethyl)-2-pyridinecarbonitrile;
2-[[(1R,3S)-3-amino-4-hydroxy-1-phenylbutyl]thio]-6-(difluoromethyl)-3-pyridinecarbonitrile;
2-[[(1R,3S)-3-amino-4-hydroxy-1-phenylbutyl]thio]-6-(fluoromethyl)-3-pyridinecarbonitrile;
2-[[(1R,3S)-3-amino-4-hydroxy-1-(3-pyridinyl)butyl]oxy]-4-chloro-5-fluorobenzonitrile;
2-[[(1R,3S)-3-amino-4-hydroxy-1-(2-thiazolyl)butyl]oxy]-4-chloro-5-fluorobenzonitrile;
z-[[(1R,3S)-3-amino-4-hydroxy-1-(5-isothiazolyl)butyl]oxy]-4-chloro-5-fluorobenzonitrile;
4-[[( 1 R,3S'~-3-amino-4-hydroxy-1-phenylbutyl]thio]-6-methoxy-3-pyridinecarbonitrile;
4-[[( 1 R,3R)-3-amino-4-hydroxy-1-phenylbutyl]thio]-6-methoxy-3-pyridinecarbonitrile;
4-[[(1 S,3R)-3-amino-4-hydroxy-1-phenylbutyl]thio]-6-methoxy-3-pyridinecarbonitrile;
4-[ [( 1 S,3 S)-3-amino-4-hydroxy-1-phenylbutyl]thio]-6-methoxy-3-pyridinecarbonitrile;
4-[[( 1 R,3 S)-3-amino-4-hydroxy-1-phenylbutyl]thio]-6-(difluoromethoxy)-3-pyridinecarbonitrile;
2-[[( 1 R,3R)-3-amino-4-hydroxy-1-phenylbutyl]thio]-6-methyl-3-pyridinecarbonitrile;

4-[[(1R,3S)-3-amino-4-hydroxy-1-phenylbutyl]thio]-6-(2H3)methoxy-3-pyridinecarbonitrile;
2-[[(1R,3S)-3-amino-4-hydroxy-1-phenylbutyl]thio]-6-ethyl-3-pyridinecarbonitrile;
2-[[(1R,3S)-3-amino-4-hydroxy-1-phenylbutyl]thio]-6-(1-methylethyl)-3-pyridinecarbonitrile;
2-[[(1R,3S)-3-amino-4-hydroxy-1-phenylbutyl]thio]-6-methyl-3-pyridinemethanol;
6-acetyl-2-[[(1R,3S)-3-amino-4-hydroxy-1-phenylbutyl]thio]-3-pyridine carbonitrile;
2-[[(1R,3S)-3-amino-4-hydroxy-1-phenylbutyl]thin]-6-(hydroxymethyl)-3-pyridine carbonitrile;
2-[[(1R,3S)-3-amino-4-hydroxy-1-phenylbutyl]thio]-3-pyridinecarbonitrile;
(.beta.1S,.delta.1R)-[3-amino-8-[(2,5-dichloro-4-pyridinyl)thiobenzenebutanol];
2-[[(1R,3S)-3-amino-4-hydroxy-1-phenylbutyl]thio]-5-fluoro-6-methoxy-3-pyridinecarbonitrile;
4-[[(1R,3S)-3-amino-4-hydroxy-1-phenylbutyl]thio]-6-(dimethylamino)-3-pyridinecarbonitrile;
4-[[(1R,3S)-3-amino-4-hydroxy-1-phenylbutyl]thio]-6-(methylamino)-3-pyridinecarbonitrile;
([.beta.1S,.delta.1R)-[3-amino-5-[(5-bromo-2-methoxy-4-pyridinyl)thio]-benzenebutanol;
((.beta.1S,.delta.1R)-(3-amino-8-[(5-chloro-2-methoxy-4-pyridinyl)thio]-benzenebutanol;
4-[[(1R,3S)-3-amino-4-hydroxy-1-phenylbutyl]thio]-6-ethoxy-3-pyridinecarbonitrile;
3-[[(1R,3S)-3-amino-4-hydroxy-1-phenylbutyl]thin]-5-(trifluoromethyl)-2-pyridinecarbonitrile;
3-[[(1R,3S)-3-amino-4-hydroxy-1-phenylbutyl]thio]-1,6-dihydro-5-methyl-6-oxo-2-pyridinecarbonitrile;
3-[[(1R,3S)-3-amino-4-hydroxy-1-phenylbutyl]thio]-5-chloro-2-pyridinecarbonitrile;
6-amino-4-[[(1R,3S)-3-amino-4-hydroxy-1-phenylbutyl]thio]-3-pyridinecarbonitrile;
3-[[(1R,3S)-3-amino-4-hydroxy-1-phenylbutyl]thio]-5-methyl-2-pyridinecarbonitrile;
4-[[(1R,3S)-3-amino-1-(2-fluorophenyl)-4-hydroxybutyl]thio]-6-methoxy-3-pyridinecarbonitrile;
2-[[(1R,3S)-3-amino-1-(4-fluorophenyl)-4-hydroxybutyl]oxy]-6-trifluoromethyl-3-pyridinecarbonitrile;

2(2S)-amino-4 (4R)-(3-fluorophenyl)-4-[(4-methoxy-2-nitrophenyl)thio]butan-1-ol;
2(2S)-amino-4(4R)-(3-fluorophenyl)-4-[(4-chloro-2-nitrophenyl)thio]butan-1-ol;
2(2S)-amino-4(4R)-(3-fluorophenyl)-4-[(5-amino-4-chloro-2-nitrophenyl)thio]butan-1-ol;
2(2S)-amino-4(4R)-(3-fluorophenyl)-4-[(4-hydroxymethyl)-2-nitrophenyl)thio]butan-1-ol;
2(2S)-amino-4(4R)-(3-fluorophenyl)-4-[(4-fluoro-2-nitrophenyl)thio]butan-1-ol;
2(2S)-amino-4(4R)-(3-fluorophenyl)-4-[(3,5-dichloro-2-pyridyl)thio]butan-1-ol;
4-[[(1R,3S)-3-amino-4-hydroxy-1-phenylbutyl]thio]-3-chlorobenzonitrile;
4-chloro-2-[[(1R,3S)-3-(ethylamino)-4-hydroxy-1-(2-thiazolyl)butyl]oxy]-5-fluoro-benzonitrile;
2-[[(1R,3S)-3-amino-4-hydroxy-1-(5-thiazolyl)butyl]oxy]-5-fluoro-benzonitrile;
2-[[(1R,3S)-3-amino-4-methoxy-1-phenylbutyl]thio]-6-methyl-3-pyridinecarbonitrile;
2-[[(1R,3S)-3-amino-4-hydroxy-4-methyl-1-phenylpentyl]oxy]-4-chloro-5-fluoro benzonitrile;
2-[[(1S,3S)-3-amino-4-hydroxy-1-propylbutyl]oxy]-4-chloro-5-fluorobenzonitrile;
2-[[(1S)-1-[(2S)-2-amino-3-hydroxypropyl]pentyl]thio]-6-methyl-3-pyridinecarbonitrile;
2-[[(1S,3S)-3-amino-4-hydroxy-1-(2-methylpropyl)butyl]thio]-6-methyl-3-pyridinecarbonitrile;
2-[[(3S)-3-amino-4-hydroxy-1-(5-isoxazolyl)butyl]thio]-6-methyl-3-pyridinecarbonitrile;
2-[[(3S)-3-amino-4-hydroxy-1-(5-isoxazolyl)butyl]oxy]-6-(trifluoromethyl)-3-pyridinecarbonitrile;
2-[[3-(3S)-amino-4-hydroxy-1-(1R)-(2-thienyl)butyl]oxy]-4-chloro-5-fluorobenzonitrile;
2-[[3-(3S)-amino-4-hydroxy-1(1R)-(3-thienyl)butyl]oxy]-4-chloro-5-fluorobenzonitrile;
2-[[(1R,3S)-3-amino-4-hydroxy-1-(3-pyridinyl)butyl]thio]-4-(trifluoromethyl)benzonitrile;
2-[[(1R,3S)-3-amino-4-hydroxy-1-(5-pyrimidyl)butyl]thin]-4-chlorobenzonitrile;
2-[[(1R,3S)-3-amino-4-hydroxy-1-(3-pyridinyl)butyl]thio]-4-chloro-5-fluorobenzonitrile;
2-[[(1R,3S)-3-amino-4-hydroxy-1-(3-pyridyl)butyl]thio]-4-bromobenzonitrile;
2-[[(1R,3S)-3-amino-4-hydroxy-1-(2-thiazolyl)butyl]oxy]-5-fluoro-6-methyl-3-pyridinecarbonitrile;
4-[[(1R,3S)-3-amino-1-(3-fluoro-2-thienyl)-4-hydroxybutyl]thio]-6-methoxy-3-pyridinecarbonitrile;

2-[[(1R,3S)-3-amino-1-(4-chloro-5-thiazolyl)-4-hydroxybutyl]oxy]-4-chloro-5-fluorobenzonitrile;

2-[[(1R,3S)-3-amino-4-hydroxy-1-phenylbutyl]thio]-5-nitrobenzonitrile;

2-[[(1R,3S)-3-amino-4-hydroxy-1-phenylbutyl]thio]-5-chloro-3-pyridinecarbonitrile;

.beta.-amino-.delta.-[(4-amino-2-nitrophenyl)thio]-((.beta.1S,.delta.1R)-benzenebutanol;

2-[[(1R,3S)-3-amino-4-hydroxy-1-phenylbutyl]thio]-5-bromo-benzonitrile;
or a pharmaceutically acceptable salt, enantiomer or racemate thereof.
7. A compound of formula (I), according to any one of Claims 1 to 6, or a pharmaceutically acceptable salt, enantiomer or racemate thereof, for use as a medicament.
8. A pharmaceutical composition comprising a compound of formula (I) according to any one of Claims 1 to 6, or a pharmaceutically acceptable salt, enantiomer or racemate thereof, in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier.
9. The use of a compound of formula (I) according to any one of Claims 1 to 6, or a pharmaceutically acceptable salt, enantiomer or racemate thereof, in the manufacture of a medicament for the treatment or prophylaxis of human diseases or conditions in which inhibition of nitric oxide synthase activity is beneficial.
10. The use as claimed in Claim 9 wherein it is predominantly inducible nitric oxide synthase that is inhibited.
11. The use of a compound of formula (I) as defined in any one of Claims 1 to 6, or a pharmaceutically acceptable salt, enantiomer or racemate thereof, in the manufacture of a medicament, for the treatment or prophylaxis of inflammatory diseases.
12. The use as claimed in Claim 11 wherein the disease is inflammatory bowel disease.
13. The use as claimed in Claim 11 wherein the disease is rheumatoid arthritis.
14. The use as claimed in Claim 11 wherein the disease is osteoarthritis.
15. The use of a compound of formula (I) as defined in any one of Claims 1 to 6, or a pharmaceutically acceptable salt, enantiomer or racemate thereof, in the manufacture of a medicament, for the treatment or prophylaxis of pain.
16. The use of a compound of formula (I) as defined in any one of Claims 1 to 6, or a pharmaceutically acceptable salt, enantiomer or racemate thereof, in combination with a COX-2 inhibitor, in the manufacture of a medicament, for the treatment or prophylaxis of inflammatory diseases.
17. A method of treating, or reducing the risk of, human diseases or conditions in which inhibition of nitric oxide synthase activity is beneficial which comprises administering a therapeutically effective amount of a compound of formula (I), as defined in any one of Claims 1 to 6, or a pharmaceutically acceptable salt, enantiomer or racemate thereof, to a person suffering from, or at increased risk of, such diseases or conditions.
18. A method of treatment according to Claim 17 in which it is predominantly inducible nitric oxide synthase that is inhibited.
19. A method of treating, or reducing the risk of, inflammatory disease in a person suffering from, or at risk of, said disease, wherein the method comprises administering to the person a therapeutically effective amount of a compound of formula (I), as defined in any one of Claims 1 to 6, or a pharmaceutically acceptable salt, enantiomer or racemate thereof.
20. The method of treatment as claimed in Claim 19 wherein the disease is inflammatory bowel disease.
21. The method of treatment as claimed in Claim 19 wherein the disease is rheumatoid arthritis.
22. The method of treatment as claimed in Claim 19 wherein the disease is osteoarthritis.
23. A method of treating, or reducing the risk of, pain in a person suffering from, or at risk of, said condition, wherein the method comprises administering to the person a therapeutically effective amount of a compound of formula (I), as defined in any one of Claims 1 to 4, or a pharmaceutically acceptable salt, enantiomer or racemate thereof.
24. A method of treating, or reducing the risk of, inflammatory disease in a person suffering from, or at risk of, said disease, wherein the method comprises administering to the person a therapeutically effective amount of a combination of a compound of formula (I), as defined in any one of Claims 1 to 6, or a pharmaceutically acceptable salt, enantiomer or racemate thereof, with a COX-2 inhibitor.
25. A process for the preparation of a compound of formula (I), as defined in any one of Claims 1 to 6, or a pharmaceutically acceptable salt, enantiomer or racemate thereof, wherein the process comprises:
(a) reaction of a compound of formula (II) wherein T, U, X, Y and W are as defined in Claim 1 and L1 represents a leaving group, with a compound of formula (III) wherein R1, R2, R3, R4, R5, R6 and V are as defined in Claim 1; or (b) reaction of a compound of formula (IV) wherein T, U, W, X, Y and V are as defined in Claim 1;
with a compound of formula (V) wherein R1, R2, R3, R4, R5 and R6 are as defined in Claim 1 and L2 is a leaving group;
and where desired or necessary converting the resultant compound of formula (I), or another salt thereof, into a pharmaceutically acceptable salt thereof; or converting one compound of formula (I) into another compound of formula (I); and where desired converting the resultant compound of formula (I) into an optical isomer thereof.
CA002446120A 2001-05-08 2002-05-06 Novel arylheteroalkylamine derivatives Abandoned CA2446120A1 (en)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
SE0101617A SE0101617D0 (en) 2001-05-08 2001-05-08 Novel compounds
SE0101617-9 2001-05-08
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CN1630637A (en) 2005-06-22
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